Interleukin-26: an IL-10-related cytokine produced by Th17 cells

IL-26 is classified as a member of the IL-10 cytokine family because it has limited sequence homology to IL-10 and the IL-10-related cytokines. The human IL-26 gene, IL26, is located on chromosome 12q15 between the genes for two other important class-2 cytokines, IFNG (IFN-γ) and IL22 (IL-22). IL-26 is often co-expressed with IL-22 by activated T cells, especially Th17 cells. It signals through a heterodimeric receptor complex composed of the IL-20R1 and IL-10R2 chains. IL-26 receptors are primarily expressed on non-hematopoietic cell types, particularly epithelial cells. Signaling through IL-26 receptor complexes results in the activation of STAT1 and STAT3 with subsequent induction of IL-26-responsive genes. The biological functions of IL-26 have only begun to be defined.     

The family of IL-10-related cytokines and their receptors: related,but to what extent?

Five novel cytokines (IL-19, IL-20, IL-22 (IL-TIF), IL-24 (human MDA-7, mouse FISP, rat C49A/Mob-5), and IL-26 (AK155)) demonstrating limited primary sequence identity and probable structural homology to IL-10 have been identified. These cellular cytokines, as well as several cytokines encoded in viral genomes (viral cytokines), form a family of IL-10-related cytokines or the IL-10 family. These cytokines share not only homology but also receptor subunits and perhaps activities. Receptors for these cytokines belong to the class II cytokine receptor family. The receptors are IL-10R2 (CRF2-4), IL-22R1 (CRF2-9), IL-22BP (CRF2-10), IL-20R1 (CRF2-8) and IL-20R2 (CRF2-11). Biological activities of these cytokines, receptor utilization and signaling, as well as expression patterns for cytokines and their receptors are summarized. Although data indicate that these cytokines are involved in regulation of inflammatory and immune responses, their major functions remain to be discovered.     

The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis

IL-19, IL-20, IL-22, IL-24, and IL-26 are members of the IL-10 family of cytokines that have been shown to be up-regulated in psoriatic skin. Contrary to IL-10, these cytokines signal using receptor complex R1 subunits that are preferentially expressed on cells of epithelial origin; thus, we henceforth refer to them as the IL-20 subfamily cytokines. In this study, we show that primary human keratinocytes (KCs) express receptors for these cytokines and that IL-19, IL-20, IL-22, and IL-24 induce acanthosis in reconstituted human epidermis (RHE) in a dose-dependent manner. These cytokines also induce expression of the psoriasis-associated protein S100A7 and keratin 16 in RHE and cause persistent activation of Stat3 with nuclear localization. IL-22 had the most pronounced effects on KC proliferation and on the differentiation of KCs in RHE, inducing a decrease in the granular cell layer (hypogranulosis). Furthermore, gene expression analysis performed on cultured RHE treated with these cytokines showed that IL-19, IL-20, IL-22, and IL-24 regulate many of these same genes to variable degrees, inducing a gene expression profile consistent with inflammatory responses, wound healing re-epithelialization, and altered differentiation. Many of these genes have also been found to be up-regulated in psoriatic skin, including several chemokines, beta-defensins, S100 family proteins, and kallikreins. These results confirm that IL-20 subfamily cytokines are important regulators of epidermal KC biology with potentially pivotal roles in the immunopathology of psoriasis.     

New weapons in the war on worms: identification of putative mechanisms of immune-mediated expulsion of gastrointestinal nematodes

Parasitic nematode infections of humans and livestock continue to impose a significant public health and economic burden worldwide. Murine models of intestinal nematode infection have proved to be relevant and tractable systems to define the cellular and molecular basis of how the host immune system regulates resistance and susceptibility to infection. While susceptibility to chronic infection is propagated by T helper cell type 1 cytokine responses (characterised by production of IL-12, IL-18 and interferon-gamma), immunity to intestinal-dwelling adult nematode worms is critically dependent on a type 2 cytokine response (controlled by CD4+T helper type 2 cells that secrete the cytokines IL-4, IL-5, IL-9 and IL-13). However, the immune effector mechanisms elicited by type 2 cytokines in the gut microenvironment that precipitate worm expulsion have remained elusive. This review focuses on new studies that implicate host intestinal epithelial cells as one of the dominant immune effector cells against this group of pathogens. Specifically, three recently identified type 2 cytokine-dependent pathways that could offer insights into the mechanisms of expulsion of parasitic nematodes will be discussed: (i) the intelectins, a new family of galactose-binding lectins implicated in innate immunity, (ii) the resistin-like molecules, a family of small cysteine-rich proteins expressed by multiple cell types, and (iii) cytokine regulation of intestinal epithelial cell turnover. Identifying how the mammalian immune response fights gastrointestinal nematode infections is providing new insights into host protective immunity. Harnessing these discoveries, coupled with identifying what the targets of these responses are within parasitic nematodes, offers promise in the design of a new generation of anti-parasitic drugs and vaccines.     

IL-10 induces CCR6 expression during Langerhans cell development while IL-4 and IFN-gamma suppress it.

Immune responses are initiated by dendritic cells (DC) that form a network comprising different populations. In particular, Langerhans cells (LC) appear as a unique population of cells colonizing epithelial surfaces. We have recently shown that macrophage-inflammatory protein-3alpha/CCL20, a chemokine secreted by epithelial cells, induces the selective migration of LC among DC populations. In this study, we investigated the effects of cytokines on the expression of the CCL20 receptor, CCR6, during differentiation of LC. We found that both IL-4 and IFN-gamma blocked the expression of CCR6 and CCL20 responsiveness at different stages of LC development. The effect of IL-4 was reversible and most likely due to the transient blockade of LC differentiation. In contrast, IFN-gamma-induced CCR6 loss was irreversible and was concomitant to the induction of DC maturation. When other cytokines involved in DC and T cell differentiation were tested, we found that IL-10, unlike IL-4 and IFN-gamma, maintained CCR6 expression. The effect of IL-10 was reversible and upon IL-10 withdrawn, CCR6 was lost concomitantly to final LC differentiation. In addition, IL-10 induced the expression of CCR6 and responsiveness to CCL20 in differentiated monocytes that preserve their ability to differentiate into mature DC. Finally, TGF-beta, which induces LC differentiation, did not alter early CCR6 expression, but triggered its irreversible down-regulation, in parallel to terminal LC differentiation. Taken together, these results suggest that the recruitment of LC at epithelial surface might be suppressed during Th1 and Th2 immune responses, and amplified during regulatory immune responses involving IL-10 and TGF-beta.     

Interleukin-20 targets renal cells and is associated with chronic kidney disease

Interleukin (IL)-10 is an anti-inflammatory factor that suppresses renal fibrosis and improves renal function in CKD rats. IL-20 belongs to the IL-10 family; therefore, we sought to determine whether IL-20 is involved in CKD. CKD patients at stage five expressed significantly higher IL-20 in serum than controls. Immunohistochemical staining demonstrated that more IL-20 protein was expressed in the kidney tubular-epithelial cells, mesangial cells, and immune cells of CKD rats with a 5/6 nephrectomy. The lung, liver, and heart tissue of CKD rats also overexpressed IL-20. Thus, we treated two tubular epithelial cells, TKPTS and M-1 cells, with IL-20 to study its effects on CKD. IL-20 treatment induced apoptosis in these cells via caspase-3 activation. Incubating IL-20 with rat interstitial fibroblasts, NRK-49F cells, upregulated TGF-β1production, one key inducer for renal fibrogenesis. Therefore, IL-20 injured renal epithelial cells and induced fibroblasts to produce TGF-β1 that hastened the progression of CKD.     

IL-36 family cytokines in protective versus destructive inflammation

The IL-1 family of cytokines and receptors are critical regulators of inflammation. Within the IL-1 family and in contrast to its IL-1 and IL-18 subfamilies, the IL-36 subfamily is still poorly characterized. Three pro-inflammatory agonists IL-36α, IL-36β, IL-36γ, one IL-36 receptor (IL-1R6) antagonist, IL-36RA, and one putative IL-1R6 antagonist, IL-38, have been grouped into the IL-36 cytokine subfamily. IL-36 agonists signal through a common receptor complex to serve as early triggers of inflammatory responses by activating and cross-regulating a number of inflammatory pathways including NF-κB, MAPK and IFN signaling. IL-36RA binds to IL-1R6 to limit inflammatory signaling, while IL-38 may be an antagonist of more than one IL-1 family receptor. Expression patterns of IL-36 family cytokines, being most prominently expressed in epithelial barrier tissues such as the skin and intestines as well as in immune cells, suggest a role in protecting these barriers from infection. Dysregulation of IL-36 family cytokine signaling at physiological barriers, most prominently the skin, induces autoimmune inflammation. However, transferring the potential of IL-36 to induce tissue damage to tumors might benefit cancer patients. Here we summarize signaling pathways regulated by IL-36 family cytokines, including IL-38, and the consequences for physiological protective and pathophysiological destructive inflammation. Moreover, we discuss the limits of current knowledge on IL-36 family function to open potential avenues for research in the future.     

Caspase-1-processed IL-1 family cytokines play a vital role in driving innate IL-17

The interleukin (IL)-1 cyokine family plays a vital role in inflammatory responses during infection and in autoimmune diseases. The pro-inflammatory cytokines, IL-1β and IL-18 are members of the IL-1 family that require cleavage by caspase-1 in the inflammasome to generate the mature active cytokines. Cells of the innate immune system, including γδ T cells and invariant natural killer T (iNKT) cells respond rapidly to invading pathogens by producing inflammatory cytokines, such as IFN-γ and IL-17. IL-1β or IL-18 in combination with IL-23 can induce IL-17 production by γδ T cells without T cell receptor (TCR) engagement. IL-1β and IL-23 can also synergize to induce IL-17 production by iNKT cells. Furthermore, CD4+ αβ effector memory T cells secrete IL-17 in response to IL-23 in combination with either IL-1β or IL-18, in the absence of any TCR stimulation. The early IL-17 produced by innate cells induces recruitment of neutrophils to the site of infection, stimulates local epithelial cells to secrete anti-microbial proteins, such as lipocalins and calgranulins, induces production of structural proteins important in tight junction stability, and promotes production of matrix metalloproteinases. Caspase-1 processed IL-1 family cytokines therefore play a vital role in the innate immune response and induction of IL-17 from innate immune cells which functions to fight infections and promote autoimmunity.     

Interleukin-31 and oncostatin-M mediate distinct signaling reactions and response patterns in lung epithelial cells

Lung epithelial cells are primary targets of oncostatin M (OSM) and, to a lower degree, of interleukin (IL)-6 and IL-31, all members of the IL-6 cytokine family. The OSM receptor (OSMR) signals through activation of STAT and mitogen-activated protein kinase pathways to induce genes encoding differentiated cell functions, reduce cell-cell interaction, and suppress cell proliferation. IL-31 functions through the heteromeric IL-31 receptor, which shares with OSMR the OSMRbeta subunit, but does not engage gp130, the common subunit of all other IL-6 cytokine receptors. Because the response of epithelial cells to IL-31 is unknown, the action of IL-31 was characterized in the human alveolar epithelial cell line A549 in which the expression of the ligand-binding IL-31Ralpha subunit was increased. IL-31 initiated signaling that differed from other IL-6 cytokines by the particularly strong recruitment of the STAT3, ERK, JNK, and Akt pathways. IL-31 was highly effective in suppressing proliferation by altering expression of cell cycle proteins, including up-regulation of p27(Kip1) and down-regulation of cyclin B1, CDC2, CDK6, MCM4, and retinoblastoma. A single STAT3 recruitment site (Tyr-721) in the cytoplasmic domain of IL-31Ralpha exerts a dominant function in the entire receptor complex and is critical for gene induction, morphological changes, and growth inhibition. The data suggest that inflammatory and immune reactions involving activated T-cells regulate functions of epithelial cells by IL-6 cytokines through receptor-defined signaling reactions.     

Keratinocytes as targets for interleukin-10-related cytokines: a putative role in the pathogenesis of psoriasis

Cytokines are key factors in the cross talk between the immune system and other systems including hepatic, nervous, cardiac and cutaneous systems, leading to an adaptive and integrated response of the organism to stress. They are also involved in the regulation of many processes, including hematopoiesis, the immune response and inflammation. IL-10 is one of the most important anti-inflammatory cytokines. Five cytokines structurally related to IL-10 have been described and presently form this family of cytokines: IL-19, IL-20, IL-22, IL-24 and IL-26. In contrast to IL-10, these cytokines display pro-inflammatory activities in different tissues, including skin. Indeed, some of them induce an inflammatory keratinocyte gene expression profile and an epidermis histology resembling psoriatic lesions. In this review, we discuss recent knowledge about the effects of cytokines of the IL-10 family on keratinocytes and their potential role in psoriasis, a cutaneous inflammatory disease.     

Class II cytokine receptors and their ligands: key antiviral and inflammatory modulators

Class II cytokine receptors were originally defined on the basis of sequence homologies in the extracellular domains of receptors for interferons (IFNs) and interleukin-10 (IL-10), and the ligands, known as class II cytokines, also have a common structure. More recently, a series of new receptors and cytokines that belong to this family have been discovered. The therapeutic potential of the 'old' members of this family, IFNs and IL-1, is recognized in the clinic, and the existence of structurally related molecules is raising expectations for additional clinical applications. In this review, I discuss both structural and biological data that are emerging about this family of receptors and ligands, to highlight the potential applications of modulating the activity of these cytokines.     

Cutting edge: immune cells as sources and targets of the IL-10 family members?

This study investigated the expression of five novel human IL-10-related molecules and their receptors in blood mononuclear cells. IL-19 and IL-20 were found to be preferentially expressed in monocytes. IL-22 and IL-26 (AK155) expression was exclusively detected in T cells, especially upon type 1 polarization, and in NK cells. IL-24 (melanoma differentiation-associated gene 7) expression was restricted to monocytes and T cells. Detection of these molecules in lymphocytes was predominantly linked to cellular activation. Regarding T cells, IL-26 was primarily produced by memory cells, and its expression was independent on costimulation. In contrast to the high expression of receptors for IL-10 homologs in different tissues and cell lines, monocytes and NK, B, and T cells showed clear expression only of IL-10R1, IL-10R2, and IL-20R2. In these cells, IL-20R2 might be part of a still-unknown receptor complex. Therefore, immune cells may represent a major source but a minor target of the novel IL-10 family members.     

IL-10 family of cytokines

In 2001, six immune mediators (IL-10, IL-19, IL-20, IL-22, IL-24, and IL-26) were grouped into the so-called IL-10 family of cytokines based on their similarities with respect to the structure and location of their encoding genes, their primary and secondary protein structures, and the receptor complexes used. Surprisingly, despite all these similarities, IL-10 family members possess different biological functions. The currently known facts regarding the biological effects of these six immune mediators give the impression that at least IL-10, IL-20, and IL-22 play an important role in the pathogenesis of some chronic inflammatory diseases. This review provides an overview of the most important and common aspects of the IL-10 family members.     

Evolutionary plasticity of IL-6 cytokine family

The IL-6 family of cytokines includes a variety of proteins that function not only within the immune system, but also in other organs, tissues, and types of cells, including neurons. The common evolutionary origin of the IL-6 family proteins determines similar mechanisms of reception and intracellular signaling, although their primary structures are highly variable, as well as their biological functions. We have demonstrated that the members of the IL-6 family have high evolutionary plasticity. This manifests in a high degree of population polymorphism for IL-6 family genes, as well as varying degrees of evolutionary conservation among members of the family. The degree of evolutionary conservation of IL-6 family proteins does not correlate with the mechanisms of interaction between these cytokines and their receptors.     

Interleukins 19, 20, and 24 signal through two distinct receptor complexes. Differences in receptor-ligand interactions mediate unique biological functions

Cytokines that signal through Class II receptors form a distinct family that includes the interferons and interleukin 10 (IL-10). Recent identification of several IL-10 homologs has defined a cytokine subfamily that includes AK155, IL-19, IL-20, IL-22, and IL-24. Within this subfamily, IL-19, IL-20, and IL-24 exhibit substantial sharing of receptor complexes; all three are capable of signaling through IL-20RA/IL-20RB, and IL-20 and IL-24 both can also use IL-22R/IL-20RB. However, the biological effects of these three cytokines appear quite distinct: immune activity with IL-19, skin biology with IL-20, and tumor apoptosis with IL-24. To more fully elucidate their interactions with the receptor complexes, we have performed a series of in vitro assays. Reporter, proliferation, and direct STAT activation assays using cell lines expressing transfected receptors revealed differences between the receptor complexes. IL-19 and IL-24 also exhibited growth inhibition on a cell line endogenously expressing all three receptor subunits, an effect that was seen at cytokine levels two orders of magnitude above those required for STAT activation or proliferation. These results demonstrate that, although this subclass exhibits receptor complex redundancy, there are differences in ligand/receptor interactions and in signal transduction that may lead to specificity and a distinct biology for each cytokine.     

The Class II cytokine receptor (CRF2) family: overview and patterns of receptor-ligand interactions

Expanded genomic information has driven the discovery of new members of the human Class II family of cytokine receptors (CRF2), which now includes 12 proteins. The corresponding cytokines have been identified, paired with their receptors and initially characterized for function. These cytokines include: a new human Type I IFN, IFN-kappa; molecules related to IL-10 (IL-19, IL-20, IL-22, IL-24, IL-26); and IFN-lambdas (IL-28/29), which have antiviral and cell stimulatory activities reminiscent of Type I IFNs, but act through a distinct receptor. In response to ligand binding, the CRF2 proteins form heterodimers, leading to cytokine-specific cellular responses; these diverse physiological functions are just beginning to be explored. Progress in structural and mutational analysis of ligand-receptor interactions now presents a more reliable framework for understanding receptor-ligand interactions, and for predicting key regions in less well studied members of the CRF2 family. The relationships between the CRF2 proteins will be summarized, as will the progress in identifying patterns of receptor interactions with ligands.     

Innate responses of corneal epithelial cells against Aspergillus fumigatus challenge

Toll-like receptors (TLRs) are key components of the innate immune system that detects microbial infection and triggers host defensive responses. To determine the roles of TLR2 and TLR4 in corneal epithelial cells in mediating innate responses against Aspergillus fumigatus , telomerase-immortalized human corneal epithelial cells (THCE) were challenged by TLR2 ligand zymosan, TLR4 ligand lipopolysaccharide and A. fumigatus hyphae, respectively. Culture media were collected at different time points and enzyme-linked immunosorbent assay was performed to detect the levels of inflammatory cytokines interleukin-1β (IL-1β) and IL-6. We found that THCE responded to the challenge of TLR2 or TLR4 ligand by expressing and secreting inflammatory cytokines into the culture media. And exposure of THCE to A. fumigatus hyphae resulted in the upregulation of IL-1β and IL-6. Treatment with TLR2- or TLR4-siRNA plasmid reduced TLR2 or TLR4 expression level in THCE when compared with controls, and caused a significant decrease in A. fumigatus -induced IL-1β and IL-6 production. Our results suggested that THCE can respond to TLR2 and TLR4 ligand challenge by secreting IL-1β and IL-6. They recognize A. fumigatus hyphae via TLR2 and TLR4 and initiate innate immune responses. Corneal epithelial cells play a role in innate defense against fungal infection through the mediation of inflammatory cytokines production.     

TLR9 and RIG-I Signaling in Human Endocervical Epithelial Cells Modulates Inflammatory Responses of Macrophages and Dendritic Cells In Vitro

The innate immune system has evolved to recognize invading pathogens through pattern recognition receptors (PRRs).Among PRRs, Toll like receptors (TLRs 3, 7/8,9) and RIG-I like receptors (RLRs) have been shown to recognize viral components. Mucosal immune responses to viral infections require coordinated actions from epithelial as well as immune cells. In this respect, endocervical epithelial cells (EEC''s) play an important role in initiating innate immune responses via PRRs. It is unknown whether EEC''s can alter immune responses of macrophages and dendritic cells (DC''s) like its counterparts in intestinal and respiratory systems. In this study, we show that endocervical epithelial cells (End1/E6E7) express two key receptors, TLR9 and RIG-I involved in anti-viral immunity. Stimulation of End1/E6E7 cells lead to the activation of NF-κB and increased secretion of pro-inflammatory cytokines, IL-6 and IL-8. Polarized End1/E6E7 cells responded to apical stimulation with ligands of TLR9 and RIG-I, CpG-ODN and Poly(I:C)LL respectively, without compromising End1/E6E7 cell integrity. At steady state, spent medium from End1/E6E7 cells significantly reduced secretion of pro-inflammatory cytokines from LPS treated human primary monocyte derived macrophages (MDMs) and DC:T cell co-cultures. Spent medium from End1/E6E7 cells stimulated with ligands of TLR9/RIG-I restored secretion of pro-inflammatory cytokines as well as enhanced phagocytosis and chemotaxis of monocytic U937 cells. Spent medium from CpG-ODN and Poly(I:C)LL stimulated End1/E6E7 cells showed significant increased secretion of IL-12p70 from DC:T cell co-cultures. The anti-inflammatory effect of spent media of End1/E6E7 cell was observed to be TGF-β dependent. In summary, the results of our study indicate that EEC''s play an indispensable role in modulating anti-viral immune responses at the female lower genital tract.