Interleukin-17B Antagonizes Interleukin-25-Mediated Mucosal Inflammation

Abstract

SUMMARY The interleukin-17 (IL-17) family cytokines have emerged as critical players in inflammatory diseases. Among them, IL-25 has been shown to be important in allergic inflammation and protection against parasitic infection. Here we have demonstrated that IL-17B, a poorly understood cytokine, functions to inhibit IL-25-driven inflammation. IL-17B and IL-25, both binding to the interleukin-17 receptor B (IL-17RB), were upregulated in their expression following acute colonic inflammation. Individual inhibition of these cytokines revealed opposing functions in colon inflammation: IL-25 was pathogenic but IL-17B was protective. Similarly opposing phenotypes were observed in Citrobacter rodentium infection and allergic asthma. Moreover, IL-25 was found to promote IL-6 production from colon epithelial cells, which was inhibited by IL-17B. Therefore, our data demonstrate that IL-17B is an anti-inflammatory cytokine in the IL-17 family.

The roles and functional mechanisms of interleukin-17 family cytokines in mucosal immunity

“…25 Recently, IL-17B was demonstrated to protect mice from infection, whereas IL-17E exacerbated infectious pathogenesis in mice. 65 IL-17E and IL-17B in colitis. Il-17E expression is downregulated in inflamed colons from IBD patients and DSS-treated mice.…”

“…Recently, one study showed that IL-17B antagonized IL-17E-mediated inflammatory gene expression during colitis by inhibiting the binding of IL-17E to its receptor. 65 Although IL-17E and IL-17B bind to the same receptor, these two cytokines seem to antagonize one another through different mechanisms. The detailed signaling events mediated by these two cytokines (especially IL-17B) need to be addressed in future studies.…”

“…144 A recent study showed that IL-17E was produced by intestinal epithelial cells during acute colitis and that mice deficient in IL-17E were protected from DSS-induced colitis. 65,146 Furthermore, neutralizing IL-17E or IL-17RB with antibodies ameliorates the onset of oxazolone-induced colitis. 147 These contradictory results suggest that endogenous IL-17E signaling rather than the exogenous delivery of IL-17E might be pathogenic and contribute to intestinal inflammation.…”

“…In contrast to Il17e-deficient mice, mice deficient in the Il17b gene exhibit aggravated colitis after DSS exposure. 65 IL-17E and IL-17B in allergies. Allergic responses depend to a large extent on the production of Th2 cytokines such as IL-4, IL-5 and IL-13 in mucosal barriers.…”

Interleukin-17RA Promotes Humoral Responses and Glomerular Injury in Experimental Rapidly Progressive Glomerulonephritis

“…Although IL-17A can promote podocyte apoptosis and cytoskeletal disorganization [79,80] , IL-17A/F signalling can also promote protective immune responses against infection at epithelial surfaces [81,82] . Other IL-17 family cytokines, through engaging receptor complexes containing an IL-17RA subunit, also have protective functions at mucosal surfaces [83] . In murine diabetes, IL-17A and IL-17F protect against nephropathy and proteinuria by limiting podocyte injury through the phosphorylation of renal and hepatic AMP kinase, mediated by enhanced expression of activated microglia/macrophagerestricted whey protein domain protein in podocytes, macrophages and tubular epithelial cells, and by inducing podocyte IL-10 expression and an M2 phenotype in macrophages [84] .…”