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Bermekimab is a human-derived recombinant monoclonal antibody that exhibits immunoregulatory activity by specifically blocking interleukin-1α activity. Four phase 2 studies evaluated efficacy and safety of bermekimab in patients with moderate-to-severe atopic dermatitis (AD). In addition, a novel human skin explant model was developed to assess bermekimab pharmacokinetics/pharmacodynamics and proteomic/transcriptomic effects. Study 1 (NCT03496974, N = 38) was an open-label, dose escalation study of subcutaneous bermekimab (200 mg or 400 mg). Study 2 (NCT04021862, N = 87) was a double-blind, placebo-controlled, randomized (1:1:1) study of subcutaneous bermekimab (400 mg every week (qw) or every 2 weeks) or placebo. GENESIS (NCT04791319, N = 198) was a double-blind, placebo- and active-comparator-controlled, randomized (1:1:2:2) study of placebo, subcutaneous bermekimab (350 mg or 700 mg qw), or dupilumab. LUNA (NCT04990440, N = 6) was a double-blind, placebo-controlled, randomized (4:1) study of intravenous bermekimab 800 mg qw or placebo. A novel human ex vivo skin pharmacodynamic assay supported phase 0 (NCT03953196) and phase 1 (NCT04544813) studies. In Study 1, 400 mg subcutaneous bermekimab showed improvement in efficacy assessments (e.g., ≥ 75% improvement of EASI over baseline, IGA 0/1, and worst itch); however, efficacy was not confirmed in Study 2 or GENESIS. Consequently, GENESIS and LUNA were terminated early. The novel human ex vivo skin pharmacodynamic assay demonstrated that bermekimab reduced downstream skin injury responses. Although bermekimab showed potential as an AD treatment in preclinical and early open-label trials, larger controlled studies (Study 2 and GENESIS) did not confirm those initial results., (© 2024. The Author(s).)

Psoriasis is a chronic disorder characterized by a complex interplay between keratinocytes and inflammatory mediators. In a previous study, we evaluated diacerein's ability to diminish interleukin (IL)-1's proinflammatory effects on cultured primary human keratinocytes. In this study, we evaluated diacerein's ability to diminish the inflammatory effects of a cytokine mixture (CM) consisting of IL-17A, IL-22, oncostatin M, IL-1A, and tumor necrosis factor (TNF)-alpha on cultured primary human keratinocytes. These five cytokines have been previously shown to induce an in vivo -equivalent cell culture psoriasis model. We also evaluated diacerein's anti-inflammatory effects in comparison to and in combination with infliximab, a TNF-alpha inhibitor currently used in the treatment of psoriasis. We found 81 genes that were significantly ( P  < 0.05) dysregulated by CM compared to medium control. All three treatment groups (diacerein alone, infliximab alone, and diacerein plus infliximab) diminished the effects of CM on these genes, with the greatest effect seen with diacerein plus infliximab. Using enzyme-linked immunosorbent assay method on cell culture supernatant, we determined the protein concentration for five genes (IL-19, IL-6, CSF3, S100A8, and NAP-2) significantly ( P  < 0.05) upregulated by CM at the gene level. Diacerein alone diminished the effect of CM on the protein concentration of two genes, whereas diacerein plus infliximab diminished the effect of CM on the protein concentration of all the five genes. Based on these results, we conclude that diacerein alone or in combination with infliximab may have a therapeutic role in psoriasis by downregulating key inflammatory mediators.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and joint destruction. Although great progress has been made in the treatment of RA with antagonists of pro-inflammatory cytokines such as TNF-α, IL-6 and IL-1, the disease remains refractory in some patients. Previous studies have found that small-molecule inflammatory mediators, such as prostaglandins, leukotrienes, reactive oxygen species, nitric oxide, lipoxins and platelet-activating factor, play a significant role in the development of RA. Such compounds help to induce, maintain or reduce inflammation and could therefore be potential therapeutic targets. In this review, we describe the roles of various classes of small-molecule inflammatory mediators in RA and discuss the effects of some drugs that modulate their activity. Many drugs targeting these mediators have demonstrated good efficacy in mouse models of RA but not in patients. However, it is clear that many small-molecule inflammatory mediators play key roles in the pathogenesis of RA, and a better understanding of the underlying molecular pathways may assist in the development of targeted therapies that are efficacious in RA patients., (© 2020 The Scandinavian Foundation for Immunology.)

Candida albicans is a commensal fungus that predominantly resides on mucosal surfaces and can cause lethal systemic infection when the host defense is compromised. Candidalysin is a cytolytic peptide toxin produced by C. albicans hyphae that is essential for mucosal tissue damage and is believed to contribute to the establishment of systemic infection and mortality. Candidalysin is also required for the epithelial innate response in which proinflammatory cytokines and chemokines are produced and neutrophil recruitment is initiated. It was recently reported that epidermal growth factor receptor (EGFR) was essential for the candidalysin-triggered epithelial response. The present study identified IL-1α as another component of candidalysin-mediated initial epithelial activation. We found that human oral epithelial cells released IL-1α rapidly after candidalysin exposure. Blockade of IL-1α/IL-1 receptor (IL-1R) signaling in candidalysin-exposed cells resulted in decreased phosphorylation of IκBα, decreased induction of IκBζ and decreased production of granulocyte-macrophage colony-stimulating factor and IL-8. Expression of c-Fos, which is induced downstream of EGFR signaling in candidalysin-treated cells, is less affected by IL-1R blockade. Inversely, blockade of EGFR signaling does not affect candidalysin-mediated phosphorylation of IκBα and induction of IκBζ, suggesting that independent signaling pathways contribute to the induction of NF-κB and c-Fos downstream of the candidalysin pore formation site. Consistently, antibody inhibition of both EGFR and IL-1R enhanced the suppressive effect of cytokine production in candidalysin-treated cells. Thus, we identified the immediate release of IL-1α and its synergistic role with EGFR ligands on the initial activation of oral epithelial cells in response to candidalysin., (© The Japanese Society for Immunology. 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Most guidelines recommend the use of nonsteroidal anti-inflammatory drugs (NSAIDs), duloxetine, and tramadol for the nonoperative treatment of osteoarthritis (OA), but the use of them is limited by the tolerability and safety concerns. Lutikizumab is a novel anti-IL-1 α / β dual variable domain immunoglobulin that can simultaneously bind and inhibit IL-1 α and IL-1 β to relieve the pain and dysfunction symptoms. We conducted this network meta-analysis to comprehensively compare the clinical efficacy and safety of lutikizumab with other drugs recommended by guidelines., Methods: We conducted a Bayesian network and conventional meta-analyses to compare the efficacy and safety of lutikizumab with other traditional drugs. All eligible randomized clinical trials, in PubMed, CNKI, EMBASE, and Web of Science databases, from January 2000 to January 2020, were included. The Cochrane risk of the bias assessment tool was used for quality assessment. Pain relief, function improvement, and risk of adverse effects (AEs) were compared in this study., Results: 24 articles with 11858 patients were included. Duloxetine (DUL) had the largest effect for pain relief (4.76, 95% CI [2.35 to 7.17]), and selective cox-2 inhibitors (SCI) were the most efficacious treatment for physical function improvement (SMD 3.94, 95% CI [2.48 to 5.40]). Lutikizumab showed no benefit compared with placebo for both pain relief (SMD 1.11, 95% CI [-2.29 to 4.52]) and function improvement (SMD 0.992, 95% CI [-0.433 to 4.25]). Lutikizumab and all other drugs are of favorable tolerance for patients in the treatment of OA compared with placebo., Conclusions: Lutikizumab, the new anti-Interleukin-1 α / β dual variable domain immunoglobulin, showed no improvement in pain or function when compared with placebo. Selective cox-2 inhibitors and duloxetine remain the most effective and safest treatment for OA. More high-quality trials are still needed to reconfirm the findings of this study., Competing Interests: The authors declare that they do not have any competing interests., (Copyright © 2020 Ziqin Cao et al.)

Secukinumab is a novel IL-17A inhibitor that has been confirmed to be effective for treating PsA and RA. Several studies have demonstrated that secukinumab also provides benefits for AS patients. Thus, we performed a meta-analysis of RCTs to evaluate the short-term efficacy and safety of secukinumab for the management of AS. The PubMed, Medline, Embase, Web of Science, and Cochrane Library databases were searched for RCTs published prior to March 2020 on the treatment of AS with secukinumab. The primary outcome was the ASAS20 response, and the secondary outcomes included the ASAS40 response, ASAS5/6 response, SF-36 PCS score, ASQoL score, and AEs. Dichotomous data were expressed as pooled RRs with 95% CIs, while continuous data were expressed as pooled MDs with 95% CIs. Subgroup analysis was conducted based on whether the AS patients previously underwent treatment with TNFi. A total of 4 RCTs with 1166 patients were included in our meta-analysis. At week 16, secukinumab 150 mg yielded significant improvements in the clinical response and patient-reported outcomes for AS patients. There was no increased risk of AEs. Consistent results were detected in the meta-analysis of secukinumab 75 mg versus a placebo. Furthermore, no significant difference was detected between the secukinumab 75 mg group and secukinumab 150 mg group. We concluded that secukinumab is effective for treating AS and generally well tolerated by AS patients in the short term, regardless of whether they previously underwent TNFi treatment. The superiority of secukinumab 150 mg over secukinumab 75 mg seems to be limited, since no significant difference in any endpoint was detected between the two groups., Competing Interests: The authors declare that there is no conflicts of interest., (Copyright © 2020 Yu Zhou et al.)

Recurrent pericarditis (RP) occurs in 15% to 30% of patients following a first episode, despite standard treatment with nonsteroidal anti-inflammatory drugs, colchicine, and corticosteroids; many patients become dependent on corticosteroids. Rilonacept (KPL-914), an interleukin-1α and β inhibitor, is in development for the treatment of RP. RHAPSODY, a double-blind, placebo-controlled, randomized-withdrawal (RW) pivotal Phase 3 trial (NCT03737110), enrolls patients 12 years or older presenting with at least a third pericarditis episode, pericarditis pain score ≥4 (11-point numeric rating scale [NRS]), and C-reactive protein ≥1 mg/dL at screening. After a subcutaneous loading dose (adults, 320 mg; children, 4.4 mg/kg), all patients receive blinded weekly subcutaneous rilonacept (adults, 160 mg; children, 2.2 mg/kg) during the run-in period. Patients must taper and discontinue concomitant pericarditis medications during the blinded run-in period and achieve clinical response (C-reactive protein ≤0.5 mg/dL and weekly average NRS ≤2.0 during the 7 days prior to and including the day of randomization) by end of the run-in (while on rilonacept monotherapy) to be randomized to either continued rilonacept or placebo in the RW period. Primary efficacy end point was time to adjudicated pericarditis recurrence during the RW period; secondary efficacy end points were proportion of patients maintaining clinical response, percentage of days with NRS ≤2, and percentage of patients with no-to-minimal pericarditis symptoms at week 16 of the RW period. Safety evaluations include adverse event monitoring, physical examinations, and laboratory tests. The RHAPSODY trial will evaluate the efficacy and safety of rilonacept in the treatment of RP to improve outcomes and patient health-related quality of life., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The objective of this study was to evaluate the safety and efficacy of bermekimab, an IL-1α inhibitor, in the treatment of hidradenitis suppurativa (HS). This study was a phase II, multicenter, open-label study of two dose cohorts of bermekimab in patients with moderate-to-severe HS who are naïve to or have failed prior anti-TNF therapy. Patients with HS (n = 42) were divided into groups A and B based on whether or not they had previously failed an anti-TNF therapy. In group A (n = 24), bermekimab was administered subcutaneously at a dose of 400 mg weekly (13 doses) in patients who had previously failed anti-TNF therapy; in group B (n = 18), bermekimab was administered subcutaneously at a dose of 400 mg weekly (13 doses) in patients who were anti-TNF naïve. Bermekimab, previously found to be effective in treating HS, was evaluated using a subcutaneous formulation in patients with HS naïve to or having failed anti-TNF therapy. There were no bermekimab-related adverse events with the exception of injection site reactions. Bermekimab was effective despite treatment history, with 61% and 63% of patients naïve to and having failed anti-TNF therapy, respectively, achieving HS clinical response after 12 weeks of treatment. A significant reduction in abscesses and inflammatory nodules of 60% (P < 0.004) and 46% (P < 0.001) was seen in anti-TNF naïve and anti-TNF failure groups, respectively. Clinically and statistically significant reduction was seen in patients experiencing pain, with the Visual Analogue Scale pain score reducing by 64% (P < 0.001) and 54% (P < 0.001) in the anti-TNF naïve and anti-TNF failure groups, respectively. IL-1α is emerging as an important clinical target for skin disease, and bermekimab may represent a new therapeutic option for treating moderate-to-severe HS., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The inflammatory effects of IL-1α/β are controlled by IL-1R antagonist (IL-1Ra). One IL-1Ra isoform is secreted, whereas three other isoforms (intracellular IL-1Ra [icIL-1Ra] 1, 2, and 3) are supposed to remain intracellular because of the absence of a signal peptide. In contrast to the well-characterized function of the secreted isoform, the biological role of the intracellular isoforms remains largely unclear. icIL-1Ra1 represents the major isoform in keratinocytes. We created icIL-1Ra1 -/- mice and investigated the role of icIL-1Ra1 in Aldara (5% imiquimod)-induced psoriasis-like skin inflammation. Naive icIL-1Ra1 -/- mice bred habitually and exhibited a normal phenotype. icIL-1Ra1 deficiency aggravated Aldara-induced skin inflammation, as demonstrated by increased ear thickness and increased mRNA levels of key proinflammatory cytokines. No intracellular effect of icIL-1Ra1 could be detected in isolated keratinocytes using RNA-sequencing analysis; however, Aldara treatment led to caspase 1/11-, caspase 8-, and RIPK3-independent keratinocyte cell death accompanied by the release of both icIL-1Ra1 and IL-1α. Furthermore, blocking IL-1α attenuated the clinical severity of Aldara-induced ear thickening in icIL-1Ra1 -/- mice. Our data suggest that upon keratinocyte damage icIL-1Ra1 acts extracellularly as an antagonist of the alarmin IL-1α to immediately counteract its inflammatory effects., (Copyright © 2020 by The American Association of Immunologists, Inc.)

Ex vivo culture of mouse and human skin causes an inflammatory response characterized by production of multiple cytokines. We used ex vivo culture of mouse tail skin specimens to investigate mechanisms of this skin culture-induced inflammatory response. Multiplex assays revealed production of interleukin 1 alpha (IL-1α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), chemokine C-X-C motif ligand 1 (CXCL1), granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) during skin culture, and quantitative PCR revealed transcripts for these proteins were also increased. Ex vivo cultures of skin from myeloid differentiation primary response 88 deficient mice (Myd88 -/- ) demonstrated significantly reduced expression of transcripts for the aforementioned cytokines. The same result was observed with skin from interleukin 1 receptor type 1 deficient mice (Il1r1 -/- ). These data suggested the IL-1R1/MyD88 axis is required for the skin culture-induced inflammatory response and led us to investigate the role of IL-1α and IL-1β (the ligands for IL-1R1) in this process. Addition of IL-1α neutralizing antibody to skin cultures significantly reduced expression of Cxcl1, Il6 and Csf3. IL-1β neutralization did not reduce levels of these transcripts. These studies suggest that IL-1α promotes the skin the culture-induced inflammatory response., (© 2019 This article is a U.S Government work and is in the public domain in the USA.)

Background: Diaper dermatitis (DD) is the most common acute inflammatory skin disease. It has a serious effect on children's and families' quality of life. We aimed to screen and evaluate the efficacy of different formulas for relieving the diaper dermatitis symptoms by developing a kind of diaper dermatitis-like reconstructed human skin equivalent in vitro., Materials and Method: We developed the human skin equivalent for diaper dermatitis with 0.2% Sodium lauryl sulfate (SLS). The diaper dermatitis-like human skin equivalent was characterized by high level of inflammation, such as overexpression of interleukin-1α (IL-1α), and impaired skin barrier. Four formulas with potential of anti-inflammation and promotion of skin barrier function were topically applied on the diaper dermatitis-like human skin equivalent surface. The afterward protection efficacy was evaluated by endpoints of IL-1α, tissue viability, and skin barrier function., Results: The chemical irritant induced high release of IL-1α, impaired tissue viability, and skin barrier function. The cream prepared with potential of anti-inflammation and skin protection could effectively decrease and relive the impact of irritant with decreased level of IL-1α and the higher tissue viability than the placebo exposure., Conclusion: The results showed that diaper dermatitis-like human skin equivalent induced by SLS can mimic the skin irritation response of the diaper rash., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

After cutaneous injury, keratinocytes secrete paracrine factors that regulate wound cell functions; dysregulation of this signaling can lead to wound pathologies. Previously, we established that keratinocyte integrin α3β1 promotes wound angiogenesis through paracrine stimulation of endothelial cells. We hypothesize here that α3β1-dependent paracrine signaling from keratinocytes regulates the differentiation state of myofibroblasts. We report that epidermal α3-knockout mice exhibit more wound myofibroblasts and fewer cyclooxygenase 2 (Cox-2)-positive dermal cells than controls. We also found that conditioned medium from α3-expressing mouse keratinocytes (MKα3 + ), but not from α3-null MK cells (MKα3 - ), induces expression of Cox-2 in fibroblasts in a time- and dose-dependent manner and that this induction is mediated by IL-1α. Compared with MKα3 - cells, MKα3 + cells secrete more IL-1α and less IL-1RA, a natural IL-1 receptor antagonist. Treatment with an IL-1α neutralizing antibody, recombinant IL-1RA, or IL-1 receptor-targeting small interfering RNA suppresses MKα3 + conditioned medium-dependent induction of Cox-2 expression in fibroblasts. Finally, active recombinant IL-1α is sufficient to induce Cox-2 in fibroblasts and to inhibit transforming growth factor-β-induced α-SMA expression. Our findings support a role for keratinocyte integrin α3β1 in controlling the secretion of IL-1α, a paracrine factor that regulates the wound myofibroblast phenotype., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Targeting interleukin-1 (IL-1) represents a novel therapeutic approach to atherosclerosis. CANTOS demonstrated the benefits of IL-1β neutralization in patients post-myocardial infarction with residual inflammatory risk. Yet, some mouse data have shown a prominent role of IL-1α rather than IL-1β in atherosclerosis, or even a deleterious effect of IL-1 on outward arterial remodelling in atherosclerosis-susceptible mice. To shed light on these disparate results, this study investigated the effect of neutralizing IL-1α or/and IL-1β isoforms starting either early in atherogenesis or later in ApoE-/- mice with established atheroma., Methods and Results: The neutralization of IL-1α or of both IL-1 isoforms impaired outward remodelling during early atherogenesis as assessed by micro-computed tomographic and histologic assessment. In contrast, the neutralization of IL-1β did not impair outward remodelling either during early atherogenesis or in mice with established lesions. Interleukin-1β inhibition promoted a slant of blood monocytes towards a less inflammatory state during atherogenesis, reduced the size of established atheromata, and increased plasma levels of IL-10 without limiting outward remodelling of brachiocephalic arteries., Conclusion: This study established a pivotal role for IL-1α in the remodelling of arteries during early experimental atherogenesis, whereas IL-1β drives inflammation during atherogenesis and the evolution of advanced atheroma in mice., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Objective: To assess the efficacy and safety of the anti-interleukin-1α/β (anti-IL-1α/β) dual variable domain immunoglobulin lutikizumab (ABT-981) in patients with knee osteoarthritis (OA) and evidence of synovitis., Methods: Patients (n = 350; 347 analyzed) with Kellgren/Lawrence grade 2-3 knee OA and synovitis (determined by magnetic resonance imaging [MRI] or ultrasound) were randomized to receive placebo or lutikizumab 25, 100, or 200 mg subcutaneously every 2 weeks for 50 weeks. The coprimary end points were change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score at week 16 and change from baseline in MRI-assessed synovitis at week 26., Results: The WOMAC pain score at week 16 had improved significantly versus placebo with lutikizumab 100 mg (P = 0.050) but not with the 25 mg or 200 mg doses. Beyond week 16, the WOMAC pain score was reduced in all groups but was not significantly different between lutikizumab-treated and placebo-treated patients. Changes from baseline in MRI-assessed synovitis at week 26 and other key symptom- and most structure-related end points at weeks 26 and 52 were not significantly different between the lutikizumab and placebo groups. Injection site reactions, neutropenia, and discontinuations due to neutropenia were more frequent with lutikizumab versus placebo. Reductions in neutrophil and high-sensitivity C-reactive protein levels plateaued with lutikizumab 100 mg, with further reductions not observed with the 200 mg dose. Immunogenic response to lutikizumab did not meaningfully affect systemic lutikizumab concentrations., Conclusion: The limited improvement in the WOMAC pain score and the lack of synovitis improvement with lutikizumab, together with published results from trials of other IL-1 inhibitors, suggest that IL-1 inhibition is not an effective analgesic/antiinflammatory therapy in most patients with knee OA and associated synovitis., (© 2019, American College of Rheumatology.)

Objective: Gangliosides, ubiquitously existing membrane components that modulate transmembrane signaling and mediate cell-to-cell and cell-to-matrix interactions, are key molecules of inflammatory and neurological disorders. However, the functions of gangliosides in the cartilage degradation process remain unclear. We investigated the functional role of gangliosides in cartilage metabolism related to osteoarthritis (OA) pathogenesis., Design: We generated knockout (KO) mice by targeting the β1, 4-N-acetylgalactosaminyltransferase (GalNAcT) gene, which encodes an enzyme of major gangliosides synthesis, and the GD3 synthase (GD3S) gene, which encodes an enzyme of partial gangliosides synthesis. In vivo OA and in vitro cartilage degradation models were used to evaluate the effect of gangliosides on the cartilage degradation process., Results: The GalNAcT and GD3S KO mice developed and grew normally; nevertheless, OA changes in these mice were enhanced with aging. The GalNAcT KO mice showed significantly enhanced OA progression compared to GD3S mice in vivo. Both GalNAcT and GD3S KO mice showed severe IL-1α-induced cartilage degradation ex vivo. Phosphorylation of MAPKs was enhanced in both GalNAcT and GD3S KOs after IL-1α stimulation. Gangliosides modulated by GalNAcT or GD3S rescued an increase of MMP-13 induced by IL-1α in mice lacking GalNAcT or GD3S after exogenous replenishment in vitro., Conclusion: These data show that the deletion of gangliosides in mice enhanced OA development. Moreover, the gangliosides modulated by GalNAcT are important for cartilage metabolism, suggesting that GalNAcT is a potential target molecule for the development of novel OA treatments., (Copyright © 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Purpose of Review: Cachexia is defined as ongoing loss of skeletal muscle mass, with or without depletion of adipose tissue and is a common syndrome in cancer patients, affecting 50% of those diagnosed. Cachexia, which cannot be fully reversed and causes significant functional impairment is caused by various mechanisms such as an altered energy balance and disruption of homeostatic control by the central nervous system. This central nervous system deregulation involves hypothalamic pituitary adrenal (HPA) axis stimulation, which can be triggered by IL-1R1 engagement on neuronal processes and endothelium in the microvasculature of the hypothalamus. This review will explore current evidence regarding both the importance of IL-1α in the various components of cancer cachexia and its potential as a therapeutic target., Recent Findings: IL-1α, which signals through IL-1R1, has been identified as a key agonist in the IL-1 pathway. As such, IL-1α has been explored as a therapeutic target in cancer cachexia, leading to the development of bermekimab, a mAb which neutralizes IL-1α. With a limited array of medication currently available to treat cancer cachexia, bermekimab represents a possible therapy., Summary: IL-1α is a key mediator in cachexia development and targeting this may be a viable therapeutic target.

Diffuse activation of interleukin-1 inflammatory cytokine signaling after traumatic brain injury (TBI) elicits progressive neurodegeneration and neuropsychiatric dysfunction, and thus represents a potential opportunity for therapeutic intervention. Although interleukin (IL)-1α and IL-1β both activate the common type 1 IL-1 receptor (IL-1RI), they manifest distinct injury-specific roles in some models of neurodegeneration. Despite its potential relevance to treating patients with TBI, however, the individual contributions of IL-1α and IL-1β to TBI-pathology have not been previously investigated. To address this need, we applied genetic and pharmacologic approaches in mice to dissect the individual contributions of IL-1α, IL-β, and IL-1RI signaling to the pathophysiology of fluid percussion-mediated TBI, a model of mixed focal and diffuse TBI. IL-1RI ablation conferred a greater protective effect on brain cytokine expression and cognitive function after TBI than did individual IL-1α or IL-1β ablation. This protective effect was recapitulated by treatment with the drug anakinra, a recombinant naturally occurring IL-1RI antagonist. Our data thus suggest that broad targeting of IL-1RI signaling is more likely to reduce neuroinflammation and preserve cognitive function after TBI than are approaches that individually target IL-1α or IL-1β signaling.

Background: Currently while, topical minoxidil and oral finasteride are the only medications approved in androgenetic alopecia (AGA), the cause oriented treatment and immunsupressive treatment are being performed in telogen effluvium (TE) and alopecia areata (AA) respectively. Considering the inflammatory factors in the pathogenesis of these three nonscarring alopecia forms, we have formulated a mixture for topical usage composed of six different herbal extracts (HE) which have already known antiinflammatory and antioxidant features., Materials and Methods: In addition to performing the phytochemical analysis of HE, we detected the gene expression level of IL-1α, the crucial hair loss mediator, for the putative efficacy in nonscarring alopecia. Cell proliferation assay was performed by XTT reagent. After determination of non-cytotoxic concentration, HaCaT cells were treated with HE. RNA isolations were carried out from both non-treated and treated cell groups by using TRI-reagent. Gene expressions of IL-1α and as control GAPDH were determined by RT-qPCR analysis., Results: Results were represented as "IL-1α/GAPDH Fold Change". HE solution caused statistically significant downregulation of IL-1α gene expressions (p<0.0001), compared to untreated control cells. HE treatment ended up with 0.1900 fold change for IL-1α., Conclusion: IL-1α is a direct growth inhibitory agent in hair follicles and an important actor in the pathogenesis of AGA , TE, and AA. Considering together the vitamins, flavonoids, and trace elements identified in the phytochemical analyses and downregulation of IL-1α in HaCaT cells, our HE may be an auxiliary agent in the therapy of these three nonscarring alopecia forms.

Processes that have been linked to aging and cancer include an inflammatory milieu driven by senescent cells. Senescent cells lose the ability to divide, essentially irreversibly, and secrete numerous proteases, cytokines and growth factors, termed the senescence-associated secretory phenotype (SASP). Senescent cells that lack p53 tumor suppressor function show an exaggerated SASP, suggesting the SASP is negatively controlled by p53. Here, we show that increased p53 activity caused by small molecule inhibitors of MDM2, which promotes p53 degradation, reduces inflammatory cytokine production by senescent cells. Upon treatment with the MDM2 inhibitors nutlin-3a or MI-63, human cells acquired a senescence-like growth arrest, but the arrest was reversible. Importantly, the inhibitors reduced expression of the signature SASP factors IL-6 and IL-1α by cells made senescent by genotoxic stimuli, and suppressed the ability of senescent fibroblasts to stimulate breast cancer cell aggressiveness. Our findings suggest that MDM2 inhibitors could reduce cancer progression in part by reducing the pro-inflammatory environment created by senescent cells.

Objective: To explore the effect of interleukin-1α (IL-1α) on the senescence of human umbilical vein endothelial cells (HUVECs) and the function of high mobility group protein 1 (HMGB1).
 Methods: HUVECs were randomly divided into a control group, a IL-1α group (10 ng/mL IL-1α), a HMGB1 group (100 ng/mL HMGB1), and a HMGB1+IL-1α group (100 ng/mL of HMGB1 plus 10 ng/mL of IL-1α). Senescence associated β-galactosidase (SA β-gal) staining was used to assess the number of senescent cells, Western blot were performed to detect the protein levels of silent information regulator 1(SIRT1), and quantitative real-time PCR (qRT-PCR) was used to detect the mRNA levels of p53, p21 and p16.
 Results: Compared with the control group, the number of SA β-gal positive cells were significantly increased in the IL-1α group (P<0.05), while the expression of SIRT1 protein significantly decreased (P<0.01). Compared with the IL-1α group, the expression of SA β-gal positive cells in the HMGB1+IL-1α group was decreased and the mRNA levels of p21 and p53 were down-regulated (all P<0.05), however, there was no statistical significance in the mRNA expression of p16 (P>0.05).
 Conclusion: IL-1α can induce the senescence of HUVECs, and HMGB1 may inhibit IL-1α-induced endothelial cell senescence via p53-p21 pathway.

Objective: To investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ABT-981, a human dual variable domain immunoglobulin simultaneously targeting interleukin (IL)-1α and IL-1β, in patients with knee osteoarthritis (OA)., Method: This was a randomized, double-blind, placebo-controlled, single-center study of multiple subcutaneous (SC) injections of ABT-981 in patients with mild-to-moderate OA of the knee (NCT01668511). Three cohorts received ABT-981 (0.3, 1, or 3 mg/kg) or placebo every other week for a total of four SC injections, and one cohort received ABT-981 (3 mg/kg) or placebo every 4 weeks for a total of three SC injections. Assessment of safety and tolerability were the primary objectives. A panel of serum and urine biomarkers of inflammation and joint degradation were evaluated., Results: A total of 36 patients were randomized (ABT-981, n = 28; placebo, n = 8); 31 (86%) completed the study. Adverse event (AE) rates were comparable between ABT-981 and placebo (54% vs 63%). The most common AE reported with ABT-981 vs placebo was injection site erythema (14% vs 0%). ABT-981 significantly reduced absolute neutrophil count and serum concentrations of IL-1α/IL-1β, high-sensitivity C-reactive protein, and matrix metalloproteinase (MMP)-derived type 1 collagen. Serum concentrations of MMP-derived type 3 collagen and MMP-degraded C-reactive protein demonstrated decreasing trends with ABT-981. Antidrug antibodies were found in 37% of patients but were not associated with the incidence or severity of AEs., Conclusion: ABT-981 was generally well tolerated in patients with knee OA and engaged relevant tissue targets, eliciting an anti-inflammatory response. Consequently, ABT-981 may provide clinical benefit to patients with inflammation-driven OA., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We investigated IL-1-induced regulation of genes related to inflammation and atherogenesis in human keratinocytes and endothelial cells, and if 'diacerein', an oral IL-1 inhibiting drug currently approved for use in osteoarthritis, would reverse IL-1's effects on these cells. Primary human keratinocytes and coronary artery endothelial cells were treated with either IL-1α or IL-1β, with and without diacerein. Using PCR-array, we assessed differential gene-expression regulated by IL-1 and diacerein. We identified 34 pro-atherogenic genes in endothelial cells and 68 pro-inflammatory genes in keratinocytes significantly (p<0.05) regulated at least 2-fold by IL-1, in comparison to control. Diacerein completely or partially reversed this regulation on almost all genes. Using ELISA, we confirmed diacerein's ability to reverse IL-1-driven gene-regulation of 11 selected factors, at the protein level. The results support a novel idea that diacerein acts as an inhibitor of the pro-atherogenic and pro-inflammatory effects of IL-1. Diacerein may have therapeutic applications to diminish IL-1-induced skin inflammation in psoriasis and attenuate IL-1-induced development of atherosclerosis. Further investigation into diacerein's effect on skin inflammation, atherogenesis and cardiovascular risk in animal models or humans is warranted.

Background: Interleukin-1α (IL-1α) released by dying cells is an alarmin that activates the innate immunity. We hypothesized that after myocardial ischemia-reperfusion (I/R) injury, IL-1α amplifies the myocardial damage by activating the inflammasome and caspase-1., Methods: Adult male CD1 mice were used. The left anterior descending coronary artery was ligated for 30 minutes, after 24 hours of reperfusion. An IL-1α blocking antibody (15 μg/kg intraperitoneally) or matching vehicle was given after reperfusion. A subgroup of mice underwent sham surgery. We assessed the effects of IL-1α blockade on caspase-1 activity, infarct size, cardiac troponin I serum levels, and left ventricular fractional shortening, 24 hours after I/R., Results: I/R led to inflammasome formation, and IL-1α blockade significantly reduced inflammasome formation, reflected by a >50% reduction in caspase-1 activity versus vehicle (P = 0.03). IL-1α blockade also reduced the infarct size (-52% infarct expressed as percentage of area at risk, and -79% for cardiac troponin I serum levels, P < 0.001 vs. vehicle) and preserved the left ventricular fractional shortening (31 ± 3% vs. 25 ± 2%, P < 0.001 vs. vehicle)., Conclusion: IL-1α blockade after I/R reduces the inflammasome activation, decreases the infarct size, and preserves the left ventricular function. IL-1α blockade may therefore represent a novel therapeutic strategy to reduce I/R injury.

The interleukin (IL)-1 family of proinflammatory cytokines are thought to play a significant role in the structural progression of osteoarthritis and its associated symptoms. IL-1α and IL-1β are 2 distinct cytokines found in the cartilage, synovial membrane, and synovial fluid of patients with osteoarthritis. The aim of these studies was to evaluate the pharmacokinetics of ABT-981, a dual variable domain immunoglobulin (DVD-Ig) capable of simultaneously binding IL-1α and IL-1β, in healthy subjects and patients with osteoarthritis of the knee. Fifty-six healthy adult subjects were randomized to receive single doses of ABT-981 intravenously (0.3, 1, 3, or 10 mg/kg), subcutaneously (0.3, 1, 3 mg/kg), or matching placebo in a 3:1 ratio. Thirty-six patients with osteoarthritis of the knee were randomized to receive 4 subcutaneous ABT-981 doses of 0.3, 1, or 3 mg/kg administered every 2 weeks, 3 subcutaneous doses of ABT-981 3 mg/kg every 4 weeks, or matching placebo in a 7:2 active:placebo ratio. ABT-981 behaved similarly to conventional monoclonal antibodies following single or multiple doses with mean maximum serum concentrations 2 to 9 days after subcutaneous doses, mean terminal half-lives of 10 to 14 days, and an absolute subcutaneous bioavailability of 46%. Exposure of ABT-981 was approximately linear following single or multiple doses every 2 weeks with monoexponential decline of terminal-phase concentrations. The most common adverse events associated with ABT-981 were diarrhea and headache in healthy subjects and injection site erythema in subjects with osteoarthritis of the knee. Decreased absolute neutrophil counts were observed in response to ABT-981 administration., (© 2016, The American College of Clinical Pharmacology.)

A critical component of innate immune response to infection and tissue damage is the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome, and this pathway and its activation products have been implicated in the pathophysiology of a variety of diseases. NLRP3 inflammasome activation leads to the cleavage of pro-IL-1β and pro-IL-18, as well as the subsequent release of biologically active IL-1β, IL-18, and other soluble mediators of inflammation. In this study, we further define the pharmacology of the previously reported NLRP3 inflammasome-selective, IL-1β processing inhibitor CP-456,773 (also known as MCC950), and we demonstrate its efficacy in two in vivo models of inflammation. Specifically, we show that in human and mouse innate immune cells CP-456,773 is an inhibitor of the cellular release of IL-1β, IL-1α, and IL-18, that CP-456,773 prevents inflammasome activation induced by disease-relevant soluble and crystalline NLRP3 stimuli, and that CP-456,773 inhibits R848- and imiquimod-induced IL-1β release. In mice, CP-456,773 demonstrates potent inhibition of the release of proinflammatory cytokines following acute i.p. challenge with LPS plus ATP in a manner that is proportional to the free/unbound concentrations of the drug, thereby establishing an in vivo pharmacokinetic/pharmacodynamic model for CP-456,773. Furthermore, CP-456,773 reduces ear swelling in an imiquimod cream-induced mouse model of skin inflammation, and it reduces airway inflammation in mice following acute challenge with house dust mite extract. These data implicate the NLRP3 inflammasome in the pathogenesis of dermal and airway inflammation, and they highlight the utility of CP-456,773 for interrogating the contribution of the NLRP3 inflammasome and its outputs in preclinical models of inflammation and disease., (Copyright © 2016 by The American Association of Immunologists, Inc.)

Dysregulated wound healing is commonly associated with excessive fibrosis. Connective tissue growth factor (CTGF/CCN2) is characteristically overexpressed in fibrotic diseases and stimulated by transforming growth factor-β (TGF-β) in dermal fibroblasts. We previously showed that interleukin-1 (IL-1α) counteracts TGF-β-stimulated CTGF mRNA and protein expression in these cells. The aim of this study was to explore the effects of IL-1α on further genes and pathways in TGF-β regulated fibroblasts. Transcriptional microarray and multiple comparison analysis showed that the antagonizing effects of IL-1α was much more prominent than the synergistic effects, both with respect to number of genes and extent of changes in gene expression. Moreover, comparing canonical pathways by gene set enrichment analysis and the Ingenuity Pathway Analysis tool revealed that IL-1α counteracted TGF-β in the top six most confident pathways regulated by both cytokines. Interferon and IL-1 signaling, as well as two pathways involved in apoptosis signaling were suppressed by TGF-β and activated by IL-1α. Pathways involving actin remodeling and focal adhesion dynamics were activated by TGF-β and suppressed by IL-1α. Analyzing upstream regulators in part corroborate the comparison of canonical pathways and added cell cycle regulators as another functional group regulated by IL-1α. Finally, gene set enrichment analysis of fibrosis-related genes indicated that IL-1 moderately counteracts the collective effect of TGF-β on these genes. Microarray results were validated by qPCR. Taken together, the results indicate prominent antagonistic effects of IL-1α on TGF-β regulated interferon signaling, as well as on a wide variety of other genes and pathways in fibroblasts. J. Cell. Biochem. 117: 1622-1632, 2016. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Circulatory markers of low-grade inflammation such as tumor necrosis factor-alpha (TNF-α), interleukin-1 alpha (IL-1α), and interleukin-1 beta (IL-1β) positively correlate with endothelial damage, atheroma formation, cardiovascular disease, and aging. The natural vitamin K2-menaquinone-7 (MK-7) added to the cell culture of human monocyte-derived macrophages (hMDMs) at the same time as toll-like receptor (TLR) agonists did not influence the production of TNF-α. When the cells were pretreated up to 6 h with MK-7 before treatment with TLR agonists, MK-7 did not inhibit significantly the production of TNF-α after the TLR activation. However, 30 h pretreatment of hMDMs with at least 10 μM of MK-7 effectively and dose dependently inhibited the proinflammatory function of hMDMs. Pretreatment of hMDMs with 10 μM of MK-7 for 30 h resulted in 20% inhibition of TNF-α production after lipopolysaccharide (LPS) activation (P < .05) and 43% inhibition after macrophage-activating lipopeptide (MALP) activation (P < .001). Pathogen-associated molecular pattern (PMPP) activation was inhibited by 20% with MK-7 pretreatment; however, this inhibition was not statistically significant. The 30 h pretreatment of a THP-1-differentiated monocyte cell line with MK-7 resulted in a dose-dependent downregulation of TNFα, IL-1α, and IL-1β gene expression as evaluated by RNA semiquantitative reverse transcription polymerase chain reaction (RT-PCR). MK-7 is able to modulate immune and inflammatory reactions in the dose-response inhibition of TNF-α, IL-1α, and IL-1β gene expression and protein production by the healthy hMDMs in vitro.

Aims: The role of the IL-1 system in development of type 2 diabetes is well established. Using an IL-1 receptor antagonist, which blocks IL-1alpha and -beta activity, or by specifically neutralizing IL-1beta, several clinical studies have demonstrated improvement in insulin secretion and glycaemia. However, the role of IL-1alpha remains to be investigated., Methods: We evaluated the safety and preliminary efficacy of a neutralizing true human™ monoclonal antibody against IL-1alpha (MABp1) in an open label trial in patients with type 2 diabetes. Seven patients between 50 to 66years with type 2 diabetes mellitus were enrolled in the study. The study subjects received four biweekly intravenous infusions of MABp1 at 1.25mg/kg body weight up to day 60 and were followed up for a total of 90days., Results: Compared to baseline, after the 60-day period of treatment HbA1c was numerically reduced by 0.14±0.21% (p=0.15), fasting C-peptide was increased by 88% (p=0.03), pro-insulin by 48% (p=0.03) and insulin numerically increased by 74% (p=0.11). Systolic blood pressure numerically decreased by 11mmHg (p=0.2). Both HbA1c and blood pressure rebounded to baseline levels thirty days after the end of MABp1 application. Treatment with MABp1 was well tolerated, and no adverse events occurred during the study., Conclusion: The results point to a role of IL-1alpha in type 2 diabetes and encourage further investigations. (ClinicalTrials.gov number NCT01427699)., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Acne vulgaris is a common inflammatory skin disorder. There remain few rapid, safe, and effective therapy options for patients with moderate to severe acne vulgaris that also address psychological comorbidities such as anxiety., Objective: To assess the efficacy of interleukin 1 alpha blockade in patients with moderate to severe acne vulgaris using the true human monoclonal antibody MABp1., Methods: Eleven patients were administered open-label, subcutaneous injections of MABp1 over a six-week period. Objectives were assessment of safety, change in inflammatory lesion count and change in psychosocial functioning using two validated questionnaires., Results: There were no serious adverse events, or adverse events greater than grade I. Median inflammatory lesion counts decreased 36% (IQR -44% to 1%). Anxiety scores improved (from median 6 to 1) as well as self-image assessment (2.3±0.9 to 2.1±0.1) as measured by the Hospital Anxiety and Depression Scale and the modified Body Image Disturbance Questionnaire., Conclusion: Patients had rapid improvement of skin lesions, as well as psychosocial functioning and anxiety. MABp1 may provide a safe and effective means for treating inflammatory acne lesions and. Further studies using this antibody are warranted in this patient population.

Background: Advanced non-small cell lung cancer (NSCLC) patients were treated as part of a Phase I dose escalation and expansion study evaluating a true human monoclonal antibody targeting IL-1α (Xilonix), which is intended to modulate the malignant phenotype-inhibiting tumor growth, spread and offering relief of symptoms., Methods: Sixteen NSCLC patients were included. Patients failed a median of 4 chemotherapy regimens, including 10/16 failing anti-EGFR therapy. Disease progression was evaluated using a multi-modal approach: tumor response, patient reported outcomes (EORTC-QLQC30), and lean body mass (LBM). Patients received infusions every 2 or 3 weeks until progression, and were followed 24 months to assess survival., Results: There were no infusion reactions, dose-limiting toxicities, or deaths due to therapy. Albeit not statistically significant, there was a trend in IL-6 (-2.6 ± 18.5 (0.1 [-2.8-2.4]), platelet counts (-11 ± 54 (-4[-36.0-1.0]), CRP (-3.3 ± 30.2 (0.4 [-10.7-1.8]) and LBM (1.0 ± 2.5 (0.4 [-0.5-2.6]). Self-reported outcomes revealed reductions in pain, fatigue and improvement in appetite. Median survival was 7.6 (IQR 4.4-11.5) months, stratification based on prior anti-EGFR therapy revealed a median survival of 9.4 months (IQR 7.6-12.5) for those pretreated (N = 10) versus a survival of 4.8 months (IQR 4.3-5.7) for those without (N = 6, logrank p = 0.187)., Conclusion: Xilonix was well tolerated, with gains in LBM and improvement in symptoms suggesting a clinically important response. Although not statistically significant, the survival outcomes observed for patients with and without prior anti-EGFR therapy raises intriguing questions about the potential synergy of IL-1α blockade and anti-EGFR therapy. Further study for this agent in NSCLC is warranted.

2'-Hydroxy flavanone (1) was previously isolated from Mimosa pudica (L.) whole plant and was found to exhibit anti-inflammatory effects in vitro. There are also reports on anti-inflammatory properties of compounds bearing flavanone/chromone nucleus. Taking this into account, fourteen derivatives of 2'-hydroxy flavanone (1) were synthesized and evaluated against pro-inflammatory mediators (TNF-α, IL-1β and NO) in in vitro and in vivo models. Results directed that among the synthesized compounds, four derivatives (11-14) showed profound inhibition of pro-inflammatory mediators as compared to the lead molecule. Further, 11-14 demonstrated comparable anti-inflammatory activity with ibuprofen in carrageenan-induced rat paw edema assay and appreciable inhibition of lipopolysaccharide (LPS) induced pro-inflammatory mediators (TNF-α and IL-1β) in Sprague Dawley (SD) rats. The synthesized compounds were further subjected to molecular docking analysis and in silico prediction of pharmacokinetic properties., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Problem: Group B Streptococcus (GBS) is a leading cause of neonatal morbidity and mortality. We tested the hypothesis that the choriodecidua plays a role in GBS-stimulated human beta defensin(HBD)-2 increases in amnion cells through a secreted factor of choriodecidual origin., Method of Study: Human amnion epithelial cells were treated with choriodecidual GBS-conditioned medium, live GBS, lipoteichoic acid (LTA), or lipopolysaccharide (LPS), with and without IL-1 inhibitors., Results: Choriodecidual tissue punches released IL-1α and IL-1β in response to GBS and this medium significantly stimulated release of HBD-2 by amnion cell cultures. Inhibitors of IL-1 significantly impaired the release of HBD-2 from amnion cells treated with GBS choriodecidual conditioned medium. Direct stimulation of amnion cells with GBS, LTA, or LPS did not increase HBD-2 release., Conclusion: Paracrine signaling involving IL-1 of choriodecidual origin is likely a critical driver for amnion HBD-2 increases in response to GBS infection of extraplacental membranes., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Interleukin-1 (IL-1) cytokines such as IL-1α, IL-1β, and IL-1Ra contribute to immune regulation and inflammatory processes by exerting a wide range of cellular responses, including expression of cytokines and chemokines, matrix metalloproteinases, and nitric oxide synthetase. IL-1α and IL-1β bind to IL-1R1 complexed to the IL-1 receptor accessory protein and induce similar physiological effects. Preclinical and clinical studies provide significant evidence for the role of IL-1 in the pathogenesis of osteoarthritis (OA), including cartilage degradation, bone sclerosis, and synovial proliferation. Here, we describe the generation and characterization of ABT-981, a dual variable domain immunoglobulin (DVD-Ig) of the IgG1/k subtype that specifically and potently neutralizes IL-1α and IL-1β. In ABT-981, the IL-1β variable domain resides in the outer domain of the DVD-Ig, whereas the IL-1α variable domain is located in the inner position. ABT-981 specifically binds to IL-1α and IL-1β, and is physically capable of binding 2 human IL-1α and 2 human IL-1β molecules simultaneously. Single-dose intravenous and subcutaneous pharmacokinetics studies indicate that ABT-981 has a half-life of 8.0 to 10.4 d in cynomolgus monkey and 10.0 to 20.3 d in rodents. ABT-981 exhibits suitable drug-like-properties including affinity, potency, specificity, half-life, and stability for evaluation in human clinical trials. ABT-981 offers an exciting new approach for the treatment of OA, potentially addressing both disease modification and symptom relief as a disease-modifying OA drug.

Background: Inflammasome-activated IL-1β plays a major role in lung neutrophilic inflammation induced by inhaled silica. However, the exact mechanisms that contribute to the initial production of precursor IL-1β (pro-IL-1β) are still unclear. Here, we assessed the implication of alarmins (IL-1α, IL-33 and HMGB1) in the lung response to silica particles and found that IL-1α is a master cytokine that regulates IL-1β expression., Methods: Pro- and mature IL-1β as well as alarmins were assessed by ELISA, Western Blot or qRT-PCR in macrophage cultures and in mouse lung following nano- and micrometric silica exposure. Implication of these immune mediators in the establishment of lung inflammatory responses to silica was investigated in knock-out mice or after antibody blockade by evaluating pulmonary neutrophil counts, CXCR2 expression and degree of histological injury., Results: We found that the early release of IL-1α and IL-33, but not HMGB1 in alveolar space preceded the lung expression of pro-IL-1β and neutrophilic inflammation in silica-treated mice. In vitro, the production of pro-IL-1β by alveolar macrophages was significantly induced by recombinant IL-1α but not by IL-33. Neutralization or deletion of IL-1α reduced IL-1β production and neutrophil accumulation after silica in mice. Finally, IL-1α released by J774 macrophages after in vitro exposure to a range of micro- and nanoparticles of silica was correlated with the degree of lung inflammation induced in vivo by these particles., Conclusions: We demonstrated that in response to silica exposure, IL-1α is rapidly released from pre-existing stocks in alveolar macrophages and promotes subsequent lung inflammation through the stimulation of IL-1β production. Moreover, we demonstrated that in vitro IL-1α release from macrophages can be used to predict the acute inflammogenic activity of silica micro- and nanoparticles.

Interleukin-1 (IL-1α and IL-1β) is a prototypic, potent, multifunctional proinflammatory cytokine affecting almost all cell types. Expression of IL-1 is up regulated in different tumor phenotypes and is implicated as an important factor in tumor progression via expression of metastatic, angiogenic genes and growth factors. Therefore, down regulation of expression of IL-1 may be able to inhibit cancer progression. Mechanism of transcriptional regulation of mouse IL-1α is not yet reported. AP-1 binding site at -12 to -6 on human IL-1α promotor is highly conserved in rat IL-1α gene and regulates its expression. Based on in silico analysis, regions -12 to -6bp is found to be conserved in human and mouse IL-1α gene promotor and therefore selected to study activation of IL-1α. Further, the regions -12 to -6bp in mouse IL-1α gene promotor corresponding to AP-1 binding element show 3'→5' orientation, necessary for AP-1 binding. The present work is focused on long term effect of curcumin on expression of IL-1α and IL-1β in liver of lymphoma bearing mice. Transcriptional regulation of IL-1α and IL-1β was analyzed by AP-1 and NF-IL-6 respectively. Elevated expression and protein level of IL-1α and IL-1β were found in lymphoma bearing mice compared to normal, which were significantly down regulated by curcumin treatment. Similarly, curcumin treatment down regulated activation of IL-1α and IL-1β via AP-1 and NF-IL-6 respectively. The findings conclude that curcumin attenuates carcinogenesis by down regulating proinflammatory cytokine interleukin-1 (IL-1α and IL-1β) via modulation of AP-1 and NF-IL6 respectively in lymphoma bearing mice., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Inflammation is an important feature of the malignant phenotype and promotes angiogenesis, tumour invasiveness, metastases, and cachexia. We used a first-in-class, monoclonal antibody (MABp1) cloned from a human being to target interleukin-1α, a mediator of chronic inflammation. We aimed to assess the safety and tolerability of MABp1 for interleukin-1α blockade in a refractory cancer population., Methods: We did an open-label, dose-escalation, and phase 1 study of MABp1 in adults with metastatic cancer at the MD Anderson Clinical Center for Targeted Therapy (Houston, TX, USA). We used a standard 3+3 design to identify the maximum tolerated dose. Patients received MABp1 intravenously once every 3 weeks through four dose levels: 0.25 mg/kg, 0.75 mg/kg, 1.25 mg/kg, and 3.75 mg/kg. After the dose-escalation phase, a second dosing arm was started with dosing every 2 weeks at the maximum tolerated dose. The primary objectives were safety, tolerability, characterisation of the pharmacokinetic profile, and identification of the recommended phase 2 dose. Secondary endpoints included pharmacodynamic effects and antitumour activity. All patients who received at least one dose of MABp1 were included in the safety analyses. This trial is registered with ClinicalTrials.gov, NCT01021072., Findings: Between March 15, 2010, and July 30, 2012, 52 patients with metastatic cancer (18 tumour types) received anti-interleukin-1α monotherapy in dose-escalation and expansion groups. MABp1 was well tolerated, with no dose-limiting toxicities or immunogenicity. Thus, the recommended phase 2 dose was concluded to be 3.75 mg/kg every 2 weeks. Pharmacokinetic data were consistent at all dose levels and showed no evidence of accumulation or increased clearance of MABp1 at increasing doses. For 42 assessable patients, median plasma interleukin-6 concentrations had decreased from baseline to week 8 by a median of 2.7 pg/mL (IQR -12.6 to 3.0; p=0.08). Of the 34 patients restaged, one patient had a partial response and ten had stable disease. 30 patients were assessable for change in lean body mass, which increased by a mean of 1.02 kg (SD 2.24; p=0.02) between baseline and week 8. The most common adverse events possibly related to the study drug were proteinuria (n=11; 21%), nausea (7; 13%), and fatigue (7; 13%). The most frequent grade 3-4 adverse events (regardless of relation to treatment) were fatigue (3; 6%), dyspnoea (2; 4%), and headache (2; 4%). Two patients (4%) had grade 5 events (death due to disease progression), which were unrelated to treatment., Interpretation: MABp1 was well tolerated, no dose-limiting toxicities were experienced in this study, and disease control was observed. Further study of MABp1 anti-interleukin-1α antibody therapy for advanced stage cancer is warranted., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

IL-15 is recognized as a promising candidate for tumor immunotherapy and has been described as both a promoter of cancer and a promoter of anti-cancer immunity. IL-15 was discovered in cells transformed by HTLV-1, the etiologic agent of adult T cell leukemia/lymphoma (ATL) and the human retrovirus that carries the Tax oncogene. We have developed the TAX-LUC mouse model of ATL in which Tax expression drives both malignant transformation and luciferase expression, enabling non-invasive imaging of tumorigenesis in real time. To identify the role of IL-15 in spontaneous development of lymphoma in vivo, an IL-15(-/-) TAX-LUC strain was developed and examined. The absence of IL-15 resulted in aggressive tumor growth and accelerated mortality and demonstrated that IL-15 was not required for Tax-mediated lymphoma but was essential for anti-tumor immunity. Further analysis revealed a unique transcriptional profile in tumor cells that arise in the absence of IL-15 that included a significant increase in the expression of IL-1α and IL-1α-regulated cytokines. Moreover, anti-IL-1α antibodies and an IL-1 receptor antagonist (Anakinra) were used to interrogate the potential of IL-1α targeted therapies in this model. Taken together, these findings identify IL-15 and IL-1α as therapeutic targets in lymphoma.

IL-1 is a master cytokine of local and systemic inflammation. With the availability of specific IL-1 targeting therapies, a broadening list of diseases has revealed the pathologic role of IL-1-mediated inflammation. Although IL-1, either IL-1α or IL-1β, was administered to patients in order to improve bone marrow function or increase host immune responses to cancer, these patients experienced unacceptable toxicity with fever, anorexia, myalgias, arthralgias, fatigue, gastrointestinal upset and sleep disturbances; frank hypotension occurred. Thus it was not unexpected that specific pharmacological blockade of IL-1 activity in inflammatory diseases would be beneficial. Monotherapy blocking IL-1 activity in a broad spectrum of inflammatory syndromes results in a rapid and sustained reduction in disease severity. In common conditions such as heart failure and gout arthritis, IL-1 blockade can be effective therapy. Three IL-1blockers have been approved: the IL-1 receptor antagonist, anakinra, blocks the IL-1 receptor and therefore reduces the activity of IL-1α and IL-1β. A soluble decoy receptor, rilonacept, and a neutralizing monoclonal anti-interleukin-1β antibody, canakinumab, are also approved. A monoclonal antibody directed against the IL-1 receptor and a neutralizing anti-IL-1α are in clinical trials. By specifically blocking IL-1, we have learned a great deal about the role of this cytokine in inflammation but equally important, reducing IL-1 activity has lifted the burden of disease for many patients., (Copyright © 2013. Published by Elsevier Ltd.)

Background: Chronic periodontitis (CP) is an inflammatory disease in which cytokines play a major role in the progression of disease. Anti-inflammatory cytokines (interleukin 4 [IL-4] and IL-10) were reported to be absent or reduced in diseased periodontal tissues, suggesting an imbalance between the proinflammatory and anti-inflammatory mediators. This study tests the hypothesis that there is cellular crosstalk mediated by proinflammatory and anti-inflammatory cytokines and that blocking proinflammatory cytokine (tumor necrosis factor-α [TNF-α] and IL-1) production will enhance anti-inflammatory cytokine (IL-4 and IL-10) production from peripheral blood mononuclear cells (PBMCs) in response to Porphyromonas gingivalis., Methods: PBMCs were isolated from individuals diagnosed with CP or healthy individuals and cultured for 24 hours. Concanavalin A (ConA) was used as an activator of lymphocyte function. Live and heat-killed P. gingivalis or lipopolysaccharide from P. gingivalis were used as the bacterial stimulants. TNF-α and IL-1 production was neutralized by specific antibodies against TNF-α and IL-1α or IL-β. Culture supernatants were evaluated by enzyme-linked immunosorbent assay for TNF-α, IL-1β, IL-4, and IL-10 production., Results: Live P. gingivalis did not result in any significant IL-10 or IL-4 release, whereas heat-killed P. gingivalis led to a significant increase in IL-10 levels compared with unstimulated or live P. gingivalis-stimulated cells from both healthy individuals or those with CP. Overall, PBMCs from patients with CP produced significantly lower IL-10 in response to ConA and P. gingivalis, suggesting chronic suppression of the anti-inflammatory cytokine production. Blocking the proinflammatory cytokine response did not result in any substantial change in IL-10 or IL-4 response to live P. gingivalis. Blocking the proinflammatory cytokine response restored IL-10 production by cells from CP in response to P. gingivalis lipopolysaccharide., Conclusions: These findings suggest that PBMCs from patients with CP have suppressed anti-inflammatory cytokine production that can, in part, be restored by neutralizing proinflammatory cytokines. Monocytes are an important source of IL-10 production, and monocyte-derived IL-10 might play a regulatory role in the pathogenesis of CP.

Background: The loss of subcutaneous (sc) fat is associated with aging. Inflammatory cytokines, such as interleukin-1 α (IL-1α), interleukin-11 (IL-11) and tumor necrosis factor-α (TNF-α), are known to inhibit the differentiation of preadipocytes., Objective: This study investigated the potential role of inflammatory cytokines in solar-radiation-induced facial fat loss., Methods: Cultured fibroblasts, keratinocytes, and skin equivalents were exposed to various doses of radiation from a solar simulator. Inflammatory cytokines' mRNA production and protein secretion were examined by qRT-PCR and ELISA, respectively. In some experiments, epidermal-dermal equivalents were pretreated topically with a broad-spectrum sunscreen prior to solar simulated radiation (SSR). Human facial preadipocytes treated with recombinant IL-11 or with conditioned media from solar-irradiated equivalents were evaluated for the level of adipocyte differentiation by image analyses, Oil red O staining, and the expression of adipocyte differentiation markers., Results: IL-11, IL-1α, IL-6, and TNF-α protein secretion were induced from epidermal-dermal equivalents by exposure to SSR. A sunscreen prevented SSR-induced inflammatory cytokines production from such equivalents. Exposure of facial preadipocytes to conditioned medium from solar-irradiated epidermal-dermal equivalents inhibited their differentiation into mature adipocytes. Consequently, conditioned medium from sunscreen-pretreated, solar-irradiated equivalents did not inhibit differentiation of preadipocytes. A cocktail of neutralizing antibodies to IL-11, IL-1α, IL-6 and TNF-α significantly reduced the SSR-induced inhibition of preadipocyte differentiation., Conclusion: These results support the hypothesis that SSR-induced inflammatory cytokine may be involved in the photoaging-induced loss of facial subcutaneous fat. Inhibition of this process, e.g. by sunscreens, might slow or prevent photoaging-induced changes in facial contouring., (Copyright © 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Coenzyme Q(10) (CoQ(10) ) is a well-known antioxidant and has been used in many skincare products for anti-ageing purpose. However, the molecular mechanisms of CoQ(10) function in skin cells are not fully understood. In this paper, we compared the effects of CoQ(10) on primary human dermal fibroblasts from three individuals, including adult. We demonstrated that CoQ(10) treatment promoted proliferation of fibroblasts, increased type IV collagen expression and reduced UVR-induced matrix metalloproteinases-1 (MMP-1) level in embryonic and adult cells. In addition, CoQ(10) treatment increased elastin gene expression in cultured fibroblasts and significantly decreased UVR-induced IL-1α production in HaCat cells. Taken together, CoQ(10) presented anti-ageing benefits against intrinsic ageing as well as photo damage. Interestingly, CoQ(10) was able to inhibit tyrosinase activity, resulting in reduced melanin content in B16 cells. Thus, CoQ(10) may have potential depigmentation effects for skincare., (© 2012 Space Biology Research & Technology Center, CASC. ICS © 2012 Society of Cosmetic Scientists and the Société Française de Cosmétologie.)

Through their capacity to sense danger signals and to generate active interleukin-1β (IL-1β), inflammasomes occupy a central role in the inflammatory response. In contrast to IL-1β, little is known about how IL-1α is regulated. We found that all inflammasome activators also induced the secretion of IL-1α, leading to the cosecretion of both IL-1 cytokines. Depending on the type of inflammasome activator, release of IL-1α was inflammasome dependent or independent. Calcium influx induced by the opening of cation channels was sufficient for the inflammasome-independent IL-1α secretion. In both cases, IL-1α was released primarily in a processed form, resulting from intracellular cleavage by calpain-like proteases. Inflammasome-caspase-1-dependent release of IL-1α and IL-1β was independent of caspase-1 catalytic activity, defining a mode of action for caspase-1. Because inflammasomes contribute to the pathology of numerous chronic inflammatory diseases such as gout and diabetes, IL-1α antagonists may be beneficial in the treatment of these disorders., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Photodynamic therapy (PDT) of cancer induces oxidative stress, which intervenes in the expression of cytokines by tumor cells. The cytokines might have either a positive or a negative impact on tumor eradication. Here, we studied the expression of cytokines vascular endothelial growth factor (VEGF) and interleukin-1alpha (IL-1alpha) in the human epidermoid carcinoma A-431 cells following m-tetra(3-hydroxyphenyl)-chlorin (mTHPC)-mediated PDT in vitro and assessed the IL-1alpha effect on VEGF expression. Quantitative polymerase chain reaction and enzyme-linked immunosorbent assay revealed the enhanced production of VEGF and IL-1alpha both on mRNA and protein levels by mTHPC-loaded cells after light exposure. The silencing of IL1A by small interfering RNA resulted in decreased production of IL-1alpha and a reduced amount of VEGF. Furthermore, exogenous recombinant IL-1alpha stimulated the VEGF expression after PDT. Thus, in addition to the cytotoxic action on the A-431 cells, mTHPC-mediated PDT stimulated the production of VEGF and IL-1alpha, and IL-1alpha contributed to the VEGF overexpression. These data establish IL-1alpha as a possible target of combined cancer treatment., (© 2011 Wiley Periodicals, Inc. Photochemistry and Photobiology © 2011 The American Society of Photobiology.)

Yersinia enterocolitica is a food-borne pathogen that preferentially infects the Peyer's patches and mesenteric lymph nodes, causing an acute inflammatory reaction. Even though Y. enterocolitica induces a robust inflammatory response during infection, the bacterium has evolved a number of virulence factors to limit the extent of this response. We previously demonstrated that interleukin-1α (IL-1α) was critical for the induction of gut inflammation characteristic of Y. enterocolitica infection. More recently, the known actions of IL-1α are becoming more complex because IL-1α can function both as a proinflammatory cytokine and as a nuclear factor. In this study, we tested the ability of Y. enterocolitica to modulate intracellular IL-1α-dependent IL-8 production in epithelial cells. Nuclear translocation of pre-IL-1α protein and IL-1α-dependent secretion of IL-8 into the culture supernatant were increased during infection with a strain lacking the 70-kDa virulence plasmid compared to the case during infection with the wild type, suggesting that Yersinia outer proteins (Yops) might be involved in modulating intracellular IL-1α signaling. Infection of HeLa cells with a strain lacking the yopP gene resulted in increased nuclear translocation of pre-IL-1α and IL-1α-dependent secretion of IL-8 similar to what is observed with bacteria lacking the virulence plasmid. YopP is a protein acetylase that inhibits mitogen-activated protein kinase (MAP kinase)- and NF-κB-dependent signal transduction pathways. Nuclear translocation of pre-IL-1α and IL-1α-dependent secretion of IL-8 in response to Yersinia enterocolitica infection were dependent on extracellular signal-regulated kinase (ERK) and p38 MAP kinase signaling but independent of NF-κB. These data suggest that Y. enterocolitica inhibits intracellular pre-IL-1α signaling and subsequent proinflammatory responses through inhibition of MAP kinase pathways.