Search

Objective To investigate the effects of allergens on the expressions of IL-18, IL-18BPa and IL-18Rα protein in peripheral blood CD4+ Th1 cells of healthy control subjects (HC) and patients with allergic rhinitis (AR), and on the expressions of IL-18, IL-18BPa and IL-18Rα mRNA in the peripheral blood CD4+ T cells. Methods Blood samples were collected from patients with rhinitis for negative skin prick test (AR-), rhinitis for positive skin prick test (AR+) and HC. Flow cytometry was used to evaluate the effects of allergens on the expressions of IL-18, IL-18BPa and IL-18Rα protein in CD4+ Th1 cells. The expressions of IL-18, IL-18BPa and IL-18Rα mRNA in CD4+ T cells were determined by qPCR. Results Compared with HC, increased IL-18 while decreased IL-18BPa expressions in Th1 cells of AR- and AR+ patients were observed, increased IL-18Rα expression in Th1 cells of AR+ patients was also found. Additionally, allergens induced elevated expression of IL-18Rα protein in Th1 cells of HC, and induced elevated mRNA expressions of IL-18, IL-18BPa and IL-18Rα in isolated blood CD4+ T cells of AR+ patients and HC. Conclusion Allergens may be involved in the pathogenesis of AR by inducing the expressions of IL-18 and IL-18Rα in blood CD4+ Th1 cells. [ABSTRACT FROM AUTHOR]

Introduction: Obesity is associated with chronic inflammation. Chronic inflammation has also been linked to insulin resistance and type 2 diabetes, metabolic associated fatty liver disease, and cardiovascular disease. Glucagon-like peptide-1 (GLP-1) receptor analogs (GLP-1RA) are clinically used to treat obesity, with known anti-inflammatory properties. How the GLP-1RA exenatide effects inflammation in adolescents with obesity is not fully investigated. Methods: Forty-four patients were randomized to receive weekly subcutaneous injections with either 2 mg exenatide or placebo for 6 months. Plasma samples were collected at baseline and at the end of the study, and 92 inflammatory proteins were measured. Results: Following treatment with exenatide, 15 out of the 92 proteins were decreased, and one was increased. However, after adjustment for multiple testing, only IL-18Rα was significantly lowered following treatment. Conclusions: Weekly injections with 2 mg of exenatide lowers circulating IL-18Rα in adolescents with obesity, which may be a potential link between exenatide and its anti-inflammatory effect in vivo. This contributes to exenatide's pharmaceutical potential as a treatment for obesity beyond weight control and glucose tolerance, and should be further studied mechanistically. [ABSTRACT FROM AUTHOR]

Psoriasis is an immune-mediated inflammatory disease of the skin, which is characterized by epidermal hyperkeratosis and neutrophil infiltration. The interleukin (IL)-17/IL-23 pathway and associated cytokines play major roles in the pathogenesis and exacerbation of psoriasis. The IL-18/IL-18 receptor (R) α signaling pathway is important for Th1 cytokine production and differentiation of Th1 cells; however, its role in the pathogenesis of psoriasis remains unknown. In this study, we investigated the effect of the IL-18Rα-mediated signaling pathway in the pathogenesis of psoriasis in Il18ra-deficient mice (Il18ra−/−) and wild-type imiquimod (IMQ)-induced psoriatic dermatitis model mice. Blocking this pathway exacerbated IMQ-induced psoriatic skin inflammation. Il18ra deficiency led to significant increases in the levels of IL-1β, IL-6, IL-8, IL-17A, IL-23, and chemokine (C-X-C motif) ligand 2 in skin lesions. Gr1-positive cells highly infiltrated psoriatic skin lesions in Il18ra−/− mice compared to those in wild-type mice. Citrullinated histone H3-positive area was relatively broad in Il18ra−/− mice. These results suggest that IL-18Rα-mediated signaling pathways may inhibit psoriatic skin inflammation by regulating infiltration and activation of neutrophil and other innate immune cells.

Introduction: Mucosal-associated invariant T (MAIT) cells might play a role in B cell hyperactivity and local inflammation in primary Sjögren's syndrome (pSS), just like previously studied mucosa-associated CCR9+ and CXCR5+ T helper cells. Here, we investigated expression of CCR9, CXCR5, IL-18R and IL-7R on MAIT cells in pSS, and assessed the capacity of DMARDs to inhibit the activity of MAIT cells. Methods: Circulating CD161+ and IL-18Ra+ TCRVa7.2+ MAIT cells from pSS patients and healthy controls (HC) were assessed using flow cytometry, and expression of CCR9, CXCR5, and IL-7R on MAIT cells was studied. Production of IFN-γ and IL-21 by MAIT cells was measured upon IL-7 stimulation in the presence of leflunomide (LEF) and hydroxychloroquine (HCQ). Results: The numbers of CD161+ and IL-18Rα+ MAIT cells were decreased in pSS patients compared to HC. Relative increased percentages of CD4 MAIT cells in pSS patients caused significantly higher CD4/CD8 ratios in MAIT cells. The numbers of CCR9 and CXCR5-expressing MAIT cells were significantly higher in pSS patients. IL-7R expression was higher in CD8 MAIT cells as compared to all CD8 T cells, and changes in IL-7R expression correlated to several clinical parameters. The elevated production of IL-21 by MAIT cells was significantly inhibited by LEF/HCQ treatment. Conclusion: Circulating CD161+ and IL-18Ra+ MAIT cell numbers are decreased in pSS patients. Given their enriched CCR9/CXCR5 expression this may facilitate migration to inflamed salivary glands known to overexpress CCL25/CXCL13. Given the pivotal role of IL-7 and IL-21 in inflammation in pSS this indicates a potential role for MAIT cells in driving pSS immunopathology. [ABSTRACT FROM AUTHOR]

IntroductionMucosal-associated invariant T (MAIT) cells might play a role in B cell hyperactivity and local inflammation in primary Sjögren’s syndrome (pSS), just like previously studied mucosa-associated CCR9+ and CXCR5+ T helper cells. Here, we investigated expression of CCR9, CXCR5, IL-18R and IL-7R on MAIT cells in pSS, and assessed the capacity of DMARDs to inhibit the activity of MAIT cells.MethodsCirculating CD161+ and IL-18Rα+ TCRVα7.2+ MAIT cells from pSS patients and healthy controls (HC) were assessed using flow cytometry, and expression of CCR9, CXCR5, and IL-7R on MAIT cells was studied. Production of IFN-γ and IL-21 by MAIT cells was measured upon IL-7 stimulation in the presence of leflunomide (LEF) and hydroxychloroquine (HCQ).ResultsThe numbers of CD161+ and IL-18Rα+ MAIT cells were decreased in pSS patients compared to HC. Relative increased percentages of CD4 MAIT cells in pSS patients caused significantly higher CD4/CD8 ratios in MAIT cells. The numbers of CCR9 and CXCR5-expressing MAIT cells were significantly higher in pSS patients. IL-7R expression was higher in CD8 MAIT cells as compared to all CD8 T cells, and changes in IL-7R expression correlated to several clinical parameters. The elevated production of IL-21 by MAIT cells was significantly inhibited by LEF/HCQ treatment.ConclusionCirculating CD161+ and IL-18Rα+ MAIT cell numbers are decreased in pSS patients. Given their enriched CCR9/CXCR5 expression this may facilitate migration to inflamed salivary glands known to overexpress CCL25/CXCL13. Given the pivotal role of IL-7 and IL-21 in inflammation in pSS this indicates a potential role for MAIT cells in driving pSS immunopathology.

Objective: In asthma, genome‐wide association studies have shown that interleukin‐18 (IL‐18) receptor 1 gene (IL‐18R1) and sputum IL‐18 are increased during exacerbations. However, the role of the IL‐18 axis in bronchial epithelial function is unclear. To investigate IL‐18, IL‐18 binding protein (BP) and IL‐18R expression in bronchial biopsies and sputum samples from patients with asthma, and to determine its functional role using in vitro bronchial epithelial cells. Methods: The expression of IL‐18, IL‐18BP and IL‐18Rα was examined in subjects with asthma and healthy controls in bronchial biopsies by immunohistochemistry and IL‐18 and IL‐18BP release in sputum. In epithelial cells, the mRNA and protein expression of IL‐18, IL‐18BP, IL‐18Rα and IL‐18Rβ was assessed by qPCR, flow cytometry, Western blotting and immunofluorescence respectively. IL‐18 function in epithelial cells was examined by intracellular calcium, wound repair, synthetic activation and epithelial differentiation changes. Results: In biopsies from subjects with asthma, the IL‐18 expression was not different in the lamina propria compared with controls but was decreased in the epithelium. In contrast, the IL‐18BP was decreased in the lamina propria in asthma and was absent in the bronchial epithelium. IL‐18 was released in sputum with IL‐18BP elevated in patients with asthma. The IL‐18Rα expression was not different between health and disease. In vitro, IL‐18‐stimulated bronchial epithelial cells increased intracellular calcium, wound repair, metabolic activity, morphological changes and epithelial cellular differentiation. Conclusion: In asthma, the dynamic interaction between IL‐18, its cognate receptor and natural inhibitor is complex, with differences between airway compartments. Upregulation of IL‐18 can promote epithelial activation and cellular differentiation. [ABSTRACT FROM AUTHOR]

Abstract Objective In asthma, genome‐wide association studies have shown that interleukin‐18 (IL‐18) receptor 1 gene (IL‐18R1) and sputum IL‐18 are increased during exacerbations. However, the role of the IL‐18 axis in bronchial epithelial function is unclear. To investigate IL‐18, IL‐18 binding protein (BP) and IL‐18R expression in bronchial biopsies and sputum samples from patients with asthma, and to determine its functional role using in vitro bronchial epithelial cells. Methods The expression of IL‐18, IL‐18BP and IL‐18Rα was examined in subjects with asthma and healthy controls in bronchial biopsies by immunohistochemistry and IL‐18 and IL‐18BP release in sputum. In epithelial cells, the mRNA and protein expression of IL‐18, IL‐18BP, IL‐18Rα and IL‐18Rβ was assessed by qPCR, flow cytometry, Western blotting and immunofluorescence respectively. IL‐18 function in epithelial cells was examined by intracellular calcium, wound repair, synthetic activation and epithelial differentiation changes. Results In biopsies from subjects with asthma, the IL‐18 expression was not different in the lamina propria compared with controls but was decreased in the epithelium. In contrast, the IL‐18BP was decreased in the lamina propria in asthma and was absent in the bronchial epithelium. IL‐18 was released in sputum with IL‐18BP elevated in patients with asthma. The IL‐18Rα expression was not different between health and disease. In vitro, IL‐18‐stimulated bronchial epithelial cells increased intracellular calcium, wound repair, metabolic activity, morphological changes and epithelial cellular differentiation. Conclusion In asthma, the dynamic interaction between IL‐18, its cognate receptor and natural inhibitor is complex, with differences between airway compartments. Upregulation of IL‐18 can promote epithelial activation and cellular differentiation.

Acute myeloid leukemia (AML) constitutively express growth factors and cytokines for survival. Chemotherapy alters these signals to induce cell death. However, drug resistance in AML remains a major hindrance to successful treatment and early warning is unavailable. Modulation of signaling pathways during chemotherapy may provide a window to detect response and predict treatment outcome. Blood samples collected from AML patients before and at day-3 of induction therapy were compared for changes in expression of CD117, CD34, pro-inflammatory cytokines and mediators of Akt and MAPK pathways, using multi-color flow cytometry. Nine patients were diagnosed as drug-resistant and seven sensitive to chemotherapy. Twelve were paired. Average percentages of CD34 (66.8 ± 11.7% vs. 26.2 ± 5.8%, p = 0.033) and pBAD (66.9 ± 8.2% vs. 28.9 ± 8.2%, p = 0.016) were significantly increased in chemo-resistant (N = 9) compared to chemo-sensitive (N = 5) samples. Percentages of CD34 were strongly correlated with pBAD (R = 0.785; p = 0.001; N = 14) and pFKHR (R = 0.755; p = 0.002; N = 14) at day-3 induction. Chemo-sensitive cases expressed significantly higher percentages of IL-18Rα (71.9 ± 9.6% vs. 29.8 ± 5.8%, p = 0.016). Though not significantly different in the outcome, IL-1β was strongly associated with activated Akt-S473, IL-6 with phosphorylated JNK and FKHR while TNF-α appeared to trigger Bim, in treated samples. These preliminary results suggested AML cells resistant to chemotherapy increased expression of CD34 and may signal through pBAD while cells sensitive to chemotherapy-induced IL18Rα expression. These were observed early during induction therapy. Identifying CD34 is interesting as it is a convenient marker to monitor drug-resistance in AML patients. Inhibition of CD34 and pBAD signaling may be important in treating drug-resistant AML. [ABSTRACT FROM AUTHOR]

Psoriasis is an immune-mediated inflammatory disease of the skin, which is characterized by epidermal hyperkeratosis and neutrophil infiltration. The interleukin (IL)-17/IL-23 pathway and associated cytokines play major roles in the pathogenesis and exacerbation of psoriasis. The IL-18/IL-18 receptor (R) α signaling pathway is important for Th1 cytokine production and differentiation of Th1 cells; however, its role in the pathogenesis of psoriasis remains unknown. In this study, we investigated the effect of the IL-18Rα-mediated signaling pathway in the pathogenesis of psoriasis in Il18ra- deficient mice ( Il18ra - / - ) and wild-type imiquimod (IMQ)-induced psoriatic dermatitis model mice. Blocking this pathway exacerbated IMQ-induced psoriatic skin inflammation. Il18ra deficiency led to significant increases in the levels of IL-1β, IL-6, IL-8, IL-17A, IL-23, and chemokine (C-X-C motif) ligand 2 in skin lesions. Gr1-positive cells highly infiltrated psoriatic skin lesions in Il18ra mice. These results suggest that IL-18Rα-mediated signaling pathways may inhibit psoriatic skin inflammation by regulating infiltration and activation of neutrophil and other innate immune cells. - / - mice compared to those in wild-type mice. Citrullinated histone H3-positive area was relatively broad in Il18ra - / - mice. These results suggest that IL-18Rα-mediated signaling pathways may inhibit psoriatic skin inflammation by regulating infiltration and activation of neutrophil and other innate immune cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Akazawa, Nozaki, Yamazawa, Ishimura, Ashida, Okada, Kinoshita and Matsumura.)

Interleukin-18 (IL-18) is a pro-inflammatory cytokine and an important mediator of peripheral inflammation and host immune response. IL-18 functions through its binding with the IL-18 receptor (IL-18R), which consists of two chains, an IL-18-binding α chain (IL-18Rα) and a signaling β chain. IL-18 and IL-18R are expressed in the brain; however, limited information is available on IL-18R expression and the role of IL-18 in neurosecretory cells. In the present study, we used immunohistochemical techniques to investigate the distribution of IL-18Rα and IL-18 in the hypothalamus of male mice and rats. IL-18Rα-positive and IL-18-positive perikarya and fibers were found scattered throughout the medial septal nucleus, the nuclei of the vertical and horizontal limbs of the diagonal band, the organum vasculosum of the laminae terminalis, the preoptic area, and the anterior hypothalamic area. It is well known that gonadotropin-releasing hormone (GnRH) neuronal somata and/or fibers are found in these regions. Therefore, we performed double-label immunofluorescence for IL-18Rα/IL-18 and GnRH. IL-18Rα was expressed in approximately 60% of GnRH-immunopositive perikarya, and IL-18 was distributed in all GnRH-immunopositive perikarya. These observations suggest that IL-18 exerts direct effects upon the GnRH neuron via IL-18Rα and acts on GnRH neurons through an autocrine or paracrine pathway. [ABSTRACT FROM AUTHOR]

As an important proinflammation and immunomodulatory cytokine, IL-18 has been reported in several species of fish, but its receptor subunits, IL-18Rα and IL-18Rβ, and its decoy receptor, IL-18BP, have not been functionally characterized in fish. In the present study, IL-18Rα, IL-18Rβ and IL-18BP were cloned from rainbow trout Oncorhynchus mykiss , and they possess common conserved domains with their mammalian orthologues. In tested organs/tissues, IL-18Rα and IL-18Rβ exhibit basal expression levels, and IL-18BP has a pattern of constitutive expression. When transfected with different combinations of chimeric receptors in HEK293T cells, recombinant IL-18 (rIL-18) can induce the activation of NF-κB only when pcDNA3.1-IL-18Rα/IL-1R1 and pcDNA3.1-IL-18Rβ/IL-1RAP were both expressed. On the other hand, recombinant receptors, including rIL-18BP, rIL-18Rα-ECD-Fc and rIL-18Rβ-ECD-Fc can down-regulate significantly the activity of NF-κB, suggesting the participation of IL-18Rα, IL-18Rβ and IL-18BP in rainbow trout IL-18 signal transduction. Co-IP assays indicated that IL-18Rβ may form a complex with MyD88, IRAK4, IRAK1, TRAF6 and TAB2 in HEK293T cells, indicating that IL-18Rβ, in IL-18 signalling pathway, is associated with these signalling molecules. In conclusion, IL-18Rα, IL-18Rβ and IL-18BP in rainbow trout are conserved in function and signalling pathway with their mammalian orthologues. • IL-18Rα, IL-18Rβ and IL-18BP cloned in rainbow trout contain conserved features as their mammalian counterparts. • IL-18 functions through the receptor unites, IL-18Rα and IL-18Rβ to trigger NK-kappaB activity. • Recombinant IL-18BP, rIL-18BP, can bind with IL-18, thus reducing the IL-18 signalling. • IL-18Rβ may form a complex with MyD88, IRAK4, IRAK1, TRAF6 and TAB2 in the signalling. [ABSTRACT FROM AUTHOR]

IL-18 is induced in food allergy and EoE is food allergen-induced disease. Therefore, we tested the hypothesis whether IL-18 is involved in food allergen-induced EoE pathogenesis. Accordingly, we examined normal SPT + and SPT − EoE patient blood and biopsy samples for IL-18, IL-18Rα, ICAM and VCAM expression. Herein, we show increased IL-18 level is highly significant in food allergen SPT + compared to SPT − EoE patients. We also report that IL-18Rα + cells and mRNA levels are induced in the esophageal biopsies of EoE patients and blood IL-18 levels correlate with esophageal eosinophilia (P < 0.01). Additionally, we report that the levels of esophageal eosinophil and mast cells correlate with ICAM expression in human EoE. Mechanistically, we show that IL-18 in vitro stimulates iNKT cells and endothelial cells and induce eosinophil active cytokines IL-5 and IL-13. We provide the evidence that IL-18 is critical cytokine involved in activation of iNKT cells and ICAM in promoting human EoE. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-18 is a cytokine previously demonstrated to participate in neuroinflammatory processes. Since the components of the IL-18 receptor complex are expressed in neurons throughout the brain, IL-18 is also believed to directly influence neuronal function. Here we tested this hypothesis on mouse hippocampal neurons by measuring the effects of IL-18 on three pathways previously shown to be regulated by this cytokine in non-neuronal cells: the MAPK pathways, p38 and ERK1/2 MAPKs, STAT3 and NF-κB. Experiments were carried out in vitro using the immortalized hippocampal neuronal line HT-22 or in vivo following i.c.v. injection with recombinant mouse IL-18. We showed that IL-18 did not activate NF-κB in HT-22 cells whereas it induced a rapid (within 15min) activation of the MAPK pathways. Moreover, we demonstrated that IL-18 treatment enhanced P-STAT3 (Tyr705)/STAT3 ratio in the nucleus of HT-22 cells after 30-60min of exposure. A similar increase in P-STAT3 (Tyr705)/STAT3 ratio was observed in the whole hippocampus one hour after i.c.v. injection. These data demonstrate that IL-18 can act directly on neuronal cells affecting the STAT3 pathway; therefore, possibly regulating the expression of specific genes within the hippocampus. This effect may help to explain some of the IL-18-induced effects on synaptic plasticity and functionality within the hippocampal system. [ABSTRACT FROM AUTHOR]

IL-37 is a cytokine belonging to the IL-1 family. Although discovered in silico in 2000, significant advances in the understanding of its biology were made only in recent years. It is a member of the family with potent anti-inflammatory and immunosuppressive properties. It is produced as a precursor without a classic signal peptide. The precursor is cleaved into mature form in the cytoplasm by caspase-1. A small fraction of the cleaved IL-37 binds SMAD-3, translocates to the nucleus, and suppresses transcription of several proinflammatory genes. Both precursor and cleaved forms of IL-37 are secreted. They bind IL-18Rα chain (also used by IL-18 as a receptor subunit) and recruit Toll/IL-1R (TIR)-8 for transducing intracellular signaling. TIR-8 is a member of the IL-1 receptor family (IL-1RF) and was previously known as an orphan receptor. IL-37 suppresses activation of NF-κB and MAPK and activates Mer-PTEN-DOK pathway. It negatively regulates signaling mediated by TLR agonists, proinflammatory cytokines, and IL-1RF ligands. It also affects cell metabolism by inhibiting mTOR, GSK-3α/β, and activating AMPK. Despite having the ability to dampen host's immune responses, the cytokine has been shown to exert antitumor effects, and it has been suggested that it may act as a prognostic marker in a variety of human cancers. Recent studies have suggested that IL-37 may represent a novel therapeutic tool in patients with cancer. In this review, we provide an overview of the cytokine biology, discuss recent advances made in unraveling its anti-cancer effects, and suggest guidelines for future research., (© Society for Leukocyte Biology.)

The hallmarks of allergic bronchial asthma arise from chronic airway inflammation. Thus, elucidating the mechanisms regulating the maintenance of this chronic inflammatory response is key to understanding asthma pathogenesis. To date, it is not clear whether a predominance of proinflammatory factors or a reduced capacity of counterbalancing anti-inflammatory mediators is the pivotal factor predisposing individuals towards asthma development. The IL-1 cytokine family and its receptor systems comprise a variety of proinflammatory cytokines like IL-1β and IL-18 and anti-inflammatory molecules such as the Toll/interleukin-1 receptor 8/single Ig IL-1 receptor (IL-R)-related molecule (Tir8/SIGIRR) and the recently established cytokine IL-37. This article reviews the functions of these IL-1 cytokine family members in the regulation of allergic airway inflammation and asthma as they have been assessed clinically, in vitro and in mouse models.