Search

Sjögren's disease (SjD) is a chronic autoimmune disease characterized by focal lymphocytic inflammation in lacrimal and salivary glands. We recently identified IL-27 as a requisite signal for the spontaneous SjD-like manifestations in nonobese diabetic (NOD) mice. Here, we define T cell-intrinsic effects of IL-27 in lacrimal gland disease in NOD mice. IL-27 receptor was required by both CD4 T effector (Te) cells and CD8 T cells to mediate focal inflammation. Intrinsic IL-27 signaling was associated with PD-1 and ICOS expressing T follicular helper (Tfh)-like CD4 Te cells within lacrimal glands, including subsets defined by CD73 or CD39 expression. CD8 T cells capable of IL-27 signaling also expressed PD-1 with subsets expressing ICOS and CD73 demonstrating a T follicular cytotoxic (Tfc)-like cell phenotype and others expressing a CD39 hi exhausted-like phenotype. These findings suggest IL-27 is a key early signal driving a follicular-type response in lacrimal gland inflammation in NOD mice., Competing Interests: Declaration of competing interest All authors declare that no conflicts of interest exist., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Interleukin (IL)-22, as a member of the interleukin (IL)-10 family, is an important mediator between the immune cells and epithelial tissues during infection and inflammation. This study reported the characterization and mRNA expression patterns of Pf_IL-22 gene and its cell surface-associated receptors Pf_IL-22RA1 and soluble Pf_IL-22RA2 genes in yellow catfish (Pelteobagrus filvidraco). The open reading frames (ORFs) of the Pf_IL-22, Pf_IL-22RA1 and Pf_IL-22RA2 genes were 546 bp, 1740 bp and 690 bp in length, encoding 181, 579 and 229 amino acids, respectively. Alignments of the deduced amino acid sequences present that the Pf_IL-22 has a conserved IL-10 family signature motif, and the Pf_IL-22RA1 and Pf_IL-22RA2 have two conserved fibronectin type-III domains. Quantitative real-time PCR (qPCR) analyses showed that the Pf_IL-22 and Pf_IL-22RA1 mRNAs were highly expressed in mucosal tissues such as the fin, gill, intestine, skin mucus and stomach, and were weakly expressed in the kidney, liver and head kidney of adult yellow catfish, indicating that the Pf_IL-22 transcripts may be mainly produced by mucosal immune cells/tissues in healthy yellow catfish. The mRNA expression levels of the Pf_IL-22RA2 gene were high in the muscle and liver, and were relatively low in the spleen and kidney. The mRNA expression levels of the Pf_IL-22 and its two receptor genes were significantly up-regulated in both mucosal tissues (gill, hindgut, and skin mucus) and systemic immune tissues (spleen, head kidney and blood) after Edwardsiella ictaluri challenge. These results indicated that the Pf_IL-22 and its two receptors genes might play an important role in the innate immune defense against bacterial invasion., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Non-resolving inflammation is a major contributor to chronic disease pathogenesis, including that of cancer, chronic obstructive pulmonary disease, asthma, arthritis, inflammatory bowel disease, multiple sclerosis and obesity. Some cytokines, such as IL-1α and IL-33, may act as endogenous alarmins that contribute to non-resolving inflammation. These cytokines are constitutively expressed in the nucleus and are thought to promote inflammation only upon release during tissue damage or cell necrosis. However, the importance of their nuclear localization in immune homeostasis is not fully understood. We describe herein a novel mouse model in which the nuclear localization signal of IL-33 is abolished and demonstrate for the first time that, alone, altered subcellular localization of IL-33 dramatically affects immune homeostasis. Heterozygous IL33(tm1/+) mice display elevated serum IL-33 levels, indicating that IL-33 is constitutively released when not actively targeted to the nucleus. IL33(tm1/+) mice succumb to lethal inflammation characterized by eosinophil-dominated immune cell infiltration of multiple organs. The profound inflammatory phenotype is dependent on mediators downstream of ST2 as ST2-null mice are protected in spite of high serum IL-33 levels. Importantly, IL-33 transcript levels in this knock-in mouse model remain under endogenous control. We adopt the term "nuclear alarmin" to describe a danger signal that is primarily regulated by nuclear compartmentalization in this fashion., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

IL-36α, IL-36β, IL-36γ, and IL-36Ra, collectively called IL-36 cytokines, are part of the IL-1 family. IL-36α, IL-36β, and IL-36γ are IL-36 receptor (IL-36R) agonists, while IL-36Ra is a receptor antagonist that blocks the activation of IL-36R signaling. IL-36 cytokines require processing in order to become fully active, however the protease(s) responsible for this are currently not known. The IL-36 receptor pathway activates dendritic cells and plays a role in polarizing T-helper responses. The skin is the predominant site where IL-36 cytokines are expressed and several reports have established that they play a significant role in the pathogenesis of skin diseases. In this review the discovery and biological function of the cytokines IL-36α, IL-36β, IL-36γ and IL-36Ra will be discussed, and their role in the pathogenesis of a wide variety of diseases., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The interleukin-12 (IL-12) family comprises a group of heterodimeric cytokines and their respective receptors that play key roles in immune responses. A growing number of autoimmune diseases has been found to be associated with genetic variation in these genes. Based on their respective associations with the IL-12 genes, autoimmune diseases appear to cluster in two groups that either show strong associations with the Th1/Th17 pathway (as indicated by genetic association with IL12B and IL23R) or the Th1/IL-35 pathway as the consequence of their association with polymorphisms in the IL12A gene region. The genetic associations are described in relation to what is known of the functionality of these genes in the various diseases. Comparing association data for gene families in different diseases may lead to better insight in the function of the genes in the onset and course of the disease., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Like many cytokines, IL-27 has pleiotropic properties that can limit or enhance ongoing immune responses depending on context. Thus, under certain circumstances, IL-27 can promote TH1 differentiation and has been linked to the activation of CD8(+) T cells and enhanced humoral responses. However, IL-27 also has potent inhibitory properties and mice that lack IL-27 mediated signaling develop exaggerated inflammatory responses in the context of infection or autoimmunity. This chapter reviews in depth the biology of IL-27, including the initial discovery, characterization, and signaling mediated by IL-27 as well as more recent insights into the molecular and cellular basis for its pleiotropic effects. Many of these advances are relevant to human diseases and highlight the potential of therapies that harness the regulatory properties of IL-27., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Expression of interleukin (IL)-22, a member of the IL-10 cytokine family, has recently been reported in a number of human diseases, including mucosal-associated infections and inflammatory disorders of the intestine, skin, and joints. Both T cells and an emerging category of innate lymphoid cells are sources of IL-22, while the IL-22 receptor complex is reported to be restricted to cells of nonhematopoietic origin. The ligand-receptor distribution of IL-22-IL-22R permits immune cells to regulate responses of epithelial cells, endothelial cells, fibroblasts, and other tissue-resident stromal cells. This pathway appears to be critically important at barrier surfaces where epithelial cells play an active role in the initiation, regulation, and resolution of immune responses. Functional studies in murine model systems indicate that IL-22 has immunoregulatory properties in infection, inflammation, autoimmunity, and cancer. In these models, the functional consequences of IL-22 expression can be either pathologic or protective, depending on the context in which it is expressed. Therefore, advancing our understanding of the biology of IL-22-IL-22R may yield novel therapeutic targets in multiple human diseases. In this review, we discuss recent findings on the expression, regulation, and function of IL-22 at barrier surfaces, and offer insights into the next frontiers to be studied in this complex cytokine pathway., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Low-grade inflammation, a minor elevation in the baseline concentration of inflammatory markers such as C-reactive protein (CRP), is nowadays recognized as an important underlying condition in many common diseases. Concentrations of CRP under 10 mg/1 are called low-grade inflammation and values above that are considered as clinically significant inflammatory states. Epidemiological studies have revealed demographic and socioeconomic factors that associate with CRP concentration; these include age, sex, birth weight, ethnicity, socioeconomic status, body mass index (BMI), fiber consumption, alcohol intake, and dietary fatty acids. At the molecular level, production of CRP is induced by proinflammatory cytokines IL-1, IL-6, and IL-17 in the liver, although extra hepatic production most likely contributes to systemic concentrations. The cytokines are produced in response to, for example, steroid hormones, thrombin, C5a, bradykinin, other cytokines, UV-light, neuropeptides and bacterial components, such as lipopolysaccharide. Cytokines exert their biological effects on CRP by signaling through their receptors on hepatic cells and activating different kinases and phosphatases leading to translocation of various transcription factors on CRP gene promoter and production of CRP protein. Genetic polymorphisms in the interleukin genes as well as in CRP gene have been associated with minor elevation in CRP. As minor elevation in CRP is associated with both inflammatory and noninflammatory conditions, it should be noticed that the elevation might just reflect distressed or injured cells homeostasis maintenance in everyday life, rather than inflammation with classical symptoms of redness, swelling, heat, and pain.

We have previously shown that mutations of CD14 or TLR4 impair type I interferon (IFN) production and macrophage survival during infection with vesicular stomatitis virus (VSV). We now report that VSV glycoprotein G (gpG) is essential for the induction of a previously unrecognized CD14/TLR4-dependent response pathway in which the adapter TRAM has predominant importance, absent any need for MyD88 or Mal, and with only a partial requirement for TRIF. Downstream of TRAM, IRF7 activation leads to a type I IFN response. The pathway is utilized by myeloid dendritic cells (mDCs) and macrophages rather than plasmacytoid DCs. This new mode of TLR4 signal transduction, which does not stimulate NF-kappaB activation, reveals the importance of viral protein recognition by mDCs and shows that TLR4 can drive qualitatively different events within the cell in response to different ligands.

Interleukin-22 (IL-22) is a cytokine that regulates the production of acute phase proteins of the immunological response. On binding to its cognate receptor (IL-22R1), which is associated to the interleukin-10 receptor 2 (IL-10R2), IL-22 promotes activation of signal transducer and activator of transcription (STAT) pathway and several other cellular responses. A soluble receptor termed interleukin-22 binding protein (IL-22BP) is also able to bind to IL-22 as a natural protein antagonist, and probably provides systemic regulation of IL-22 activity. This inflammatory response system is analyzed here in terms of its molecular physiology and structural assembly. Three-dimensional (3D) model of IL-22 and structural basis of its interactions with the cognate receptors are discussed.

Chronic hepatitis C virus (HCV) infection is associated with weak CD4+ T-helper type 1 reactivity and enhanced interleukin-10 production to HCV antigens. Here we demonstrate in vitro that monoclonal antibody-induced blockade of IL-10 receptor (IL-10R) generates a favorable balance of CD4+ T-cell responses to HCV. The addition of anti-IL-10R to mononuclear cells leads to a dose-dependent increase of T-cell proliferative response to HCV core, non-structural proteins 3 and 4. In competition experiments, anti-IL-10R reversed the inhibitory effect of IL-10 on HCV-specific T-cell proliferation. Furthermore, the blockade of IL-10R altered the balance towards type 1 antiviral T-cell reactivity with an increased frequency of HCV-specific IFN-gamma producing T-cells and IFN-gamma secretion. The impact of IL-10R blockade on T-cell reactivity to HCV demonstrates the major role of IL-10 in suppressing antiviral T-cell responses. Blocking IL-10 activity may be a useful immunotherapy approach to enhance the efficacy of antiviral treatment in chronic hepatitis C.

The aim of this study was to investigate the expression of interleukin-20 (IL-20) and its receptors on psoriatic skin by immunohistochemical analysis and to evaluate the correlation of CD8-positive T lymphocytes with epidermal proliferation. Overexpression of IL-20 and its receptors was detected in the keratinocytes of the lesional skin of psoriasis and spongiotic dermatitis. The expression pattern of IL-20 spreads throughout the whole layer of epidermis, while IL-19 was expressed in up to three or four layers suprabasally. The serum level of IL-20 in psoriatic patients was significantly lower than that in healthy controls. IL-20 upregulated KGF transcripts on CD8-positive T cells. We hypothesize that overexpression of IL-20 is correlated with keratinocyte proliferation that acts through their receptor complex expressed by keratinocytes themselves. Furthermore, IL-20 can stimulate CD8-positive lymphocytes to produce KGF, which may contribute to sustaining the hyperproliferative status of the keratinocytes.

The activation of interleukin 5 (IL-5) receptor is a dynamic process that depends on specific interaction of IL-5 with IL-5 receptor alpha, the formation of oligomeric receptor complexes with receptor beta, and the initiation of cytoplasmic phosphorylation events. These steps culminate in the triggering of a cellular response. Important advances have been made recently in understanding the molecular mechanisms of cytokine recognition, receptor assembly, and signal triggering. Cytokine recognition can be envisioned by relating structure to function in IL-5 and IL-5 receptor alpha. A pair of charge-complementary regions plays an essential role in the specific interaction between IL-5 receptor alpha and IL-5. Moreover, peptide library methodology has led to the discovery of IL-5 receptor alpha antagonists that mimic key elements in IL-5 receptor recognition. Because IL-5 has been implicated in the pathology of eosinophil-related inflammatory diseases, revealing the key recognition elements of IL-5, IL-5 mimetic peptides, and IL-5 receptor alpha could help drive the design of new compounds for therapeutic treatment against allergic inflammatory diseases such as asthma.

Therapy for severe uveitis is frequently long-term immunosuppression using systemic corticosteroids and cytotoxic agents, but side effects make long-term therapy difficult. A long-term (>4 year) Phase I/II single armed interventional study using intravenous anti-IL-2 receptor alpha treatments (daclizumab) and a short-term Phase II study evaluating the use of a subcutaneous daclizumab formulation were conducted. Patients were tapered off their systemic immunosuppressive therapy and received daclizumab infusions or subcutaneous injections at intervals varying from 2 to 6 weeks. In the long-term study, seven of ten enrolled patients were tapered from their original immunosuppressive medications and maintained exclusively on repeated daclizumab infusions for control of their uveitis for over 4 years. No patient was permanently removed from therapy for an adverse event ascribed to the medication. The use of 6-week infusion intervals led to recurrence of uveitis, while 2- to 4-week intervals did not. Only one patient developed measurable anti-daclizumab antibodies but this disappeared when subcutaneous therapy was begun. In the short-term study, four of the five patients receiving the subcutaneous formulation met the study endpoints for success within the first 12 weeks. All five were successful by 26 weeks. These studies provide preliminary evidence that regularly administered long-term daclizumab therapy can be given in lieu of standard immunosuppression for years to treat severe uveitis and that subcutaneously administered daclizumab appeared to be a clinically viable treatment strategy. These studies suggest that anti-IL-2 receptor blockade could be useful in the treatment of Th1-mediated autoimmune conditions.

The growth of tumor cells can be regulated by a variety of cytokines. To investigate the pathogenesis of choriocarcinoma and explore a new therapeutic approach for the carcinoma, we examined the role of IL-6 in the growth of a human choriocarcinoma cell line (JEG-3). IL-6 was identified in the supernatant of the cell culture medium by enzyme-linked immunosorbent assay, indicating that this cell secreted IL-6. The mRNAs of IL-6, IL-6 receptor and gP130, the IL-6 signal transducer, in this cell were shown to be present by reverse transcriptase polymerase chain reaction assay and confirmed by Southern blot hybridization and direct sequencing. The addition of hrIL-6 to the cell culture failed to stimulate cell growth. Monoclonal antibodies against IL-6, IL-6 receptor, and gP130 were also unable to inhibit the proliferation of this cell line. The antisense oligonucleotides targeting IL-6 mRNA, however, inhibited both cell growth and IL-6 production. Taken together, these findings indicate that endogenous IL-6 plays an important role in the growth of the JEG-3 cell line, and it exerts its action by an intracellular autocrine growth mechanism. The results also suggest that the therapeutic trials with monoclonal antibodies designed to neutralize IL-6 or block its receptor will likely fail, whereas the antisense oligonucleotides targeted to IL-6 mRNA may have some value for the treatment of choriocarcinoma and other cancers with intracellular autocrine growth fashion mediated by IL-6.