Interleukin 25 regulates type 2 cytokine-dependent immunity and limits chronic inflammation in the gastrointestinal tract

Abstract

The cytokine interleukin (IL) 25 has been implicated in the initiation of type 2 immunity by driving the expression of type 2 cytokines such as IL-5 and IL-13, although its role in the regulation of immunity and infection-induced inflammation is unknown. Here, we identify a dual function for IL-25: first, in promoting type 2 cytokine-dependent immunity to gastrointestinal helminth infection and, second, in limiting proinflammatory cytokine production and chronic intestinal inflammation. Treatment of genetically susceptible mice with exogenous IL-25 promoted type 2 cytokine responses and immunity to Trichuris. IL-25 was constitutively expressed by CD4+ and CD8+ T cells in the gut of mouse strains that are resistant to Trichuris, and IL-25–deficient mice on a genetically resistant background failed to develop a type 2 immune response or eradicate infection. Furthermore, chronically infected IL-25−/− mice developed severe infection-induced intestinal inflammation associated with heightened expression of interferon-γ and IL-17, identifying a role for IL-25 in limiting pathologic inflammation at mucosal sites. Therefore, IL-25 is not only a critical mediator of type 2 immunity, but is also required for the regulation of inflammation in the gastrointestinal tract.

Inhibitory Effect of Recombinant IL-25 on the Development of Dextran Sulfate Sodium-Induced Experimental Colitis in Mice

“…The role for IL-17 was lately proven through neutralization of IL-17 that resulted in exacerbation of DSS-induced colitis (30). In the present study, IL-25 was not shown to play any potential role against the production of IL-17 as it was shown in chronic inflammatory studies (12,20). In that respect, our findings hinted at the possible influence of IL-25 in the induction of IL-23 and TGF-1 production but not suppression of IL-17 in the development of acute DSSinduced colitis.…”

“…**p < 0.01. compared to that of the DSS treated mice. (11,12). While an anti-inflammatory role for IL-25 was shown to be due to its ability in suppressing Th1 and Th17 responses (12), the promotion of host defense was shown to be via inhibition of expression of type 1 cytokines (11).…”

“…(11,12). While an anti-inflammatory role for IL-25 was shown to be due to its ability in suppressing Th1 and Th17 responses (12), the promotion of host defense was shown to be via inhibition of expression of type 1 cytokines (11). Yet, in a recent study, IL-25 was also reported to inhibit development and progress of inflammation in the brain and spinal cord (20).…”

“…Initially, treatment of mice with rIL-25 was shown to induce massive histological and pathological changes in the gastrointestinal (GI) tract (8). Lately, in parasitic intestinal infectious disease models, IL-25 was reported not only to limit production of pro-inflammatory cytokines but also to reduce chronic intestinal inflammation (11,12). In light of these earlier studies, we sought to evaluate the effect of rIL-25 on the development of acute DSS-induced experimental colitis.…”

Th17 cells: new players in asthma pathogenesis

“…Another possibility is the production by other cell types, such as mast cells and macrophages present in the gut of worm-infested animals or lung epithelial cells, of a more recently discovered cytokine, named as IL-25. IL-25 can induce the early production of IL-4 by a non-T, non-B, c-kit+, FceR1-cell or by the Th naı¨ve cell itself, thus allowing its Th2 polarization (52). Recent studies indicate that not only IL-4, IL-25, and Jagged-1 but also IL-33 and thymic stromal lymphopoietin (TSLP) are important mediators of Th2-cell differentiation (53)(54)(55).…”