Interleukin-23 drives innate and T cell–mediated intestinal inflammation

Abstract

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract involving aberrant activation of innate and adaptive immune responses. We have used two complementary models of IBD to examine the roles of interleukin (IL)-12 family cytokines in bacterially induced intestinal inflammation. Our results clearly show that IL-23, but not IL-12, is essential for the induction of chronic intestinal inflammation mediated by innate or adaptive immune mechanisms. Depletion of IL-23 was associated with decreased proinflammatory responses in the intestine but had little impact on systemic T cell inflammatory responses. These results newly identify IL-23 as a driver of innate immune pathology in the intestine and suggest that selective targeting of IL-23 represents an attractive therapeutic approach in human IBD.

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

“…However, further studies will be necessary to determine the actual role for TGF-1 and other TGF-1 related cytokines like IL-10 in the course of regulation of gastrointestinal tract inflammation by IL-25. Even though a number of recent studies reported a critical role for IL-23 in the pathogenesis of intestinal inflammation (26,27), the actual causes of elevation of IL-23 cytokine in these DSS-induced colitis mice treated with rIL-25 remain uncertain. However, TGF-1 has been shown to have the ability to up-regulate IL-23R expression to induce IL-23 responsiveness (28).…”

Distinct regulation of interleukin‐17 in human T helper lymphocytes

“…The current view of mouse Th17 development is that TGF␤1 and IL-6 are the key cytokines that initiate the differentiation process and that IL-23 plays an essential role in the expansion and maintenance of this lineage. Support for the notion of an IL-23/IL-17 axis has been provided by a number of models of autoimmunity (6,(8)(9)(10)(11)26,39,(44)(45)(46), but despite these compelling data in mice, a systematic analysis of human Th17 differentiation from naive cells has not yet been undertaken.…”

“…Recent studies have supported the notion of a role of IL-23 in autoimmune responses, and a preponderance of evidence indicates that this cytokine may be more clinically relevant than its close relative IL-12 in causing autoimmunity (8)(9)(10)(11)45). The recent discovery of the relationship between IL-23R single-nucleotide polymorphisms and the prevalence of inflammatory bowel disease highlights the relevance of this cytokine in human autoimmune disease (48).…”

“…Similarly, anti-p40 antibody is efficacious in the treatment of Crohn's disease (7). Although these effects were initially misattributed to interference with the actions of IL-12, using specific deletion of IL-23 (p19 Ϫ/Ϫ mice), it is now recognized that IL-23 (and not IL-12) is the culprit, at least in many of the animal models (8)(9)(10)(11)(12)(13).…”

Induction, function and regulation of IL‐17‐producing T cells

“…In addition, it was demonstrated that adoptive transfer of IL-23-polarized autoantigen-specific Th17 effector cells were able to transfer EAE more effectively than Th1 cells [9]. IL-17 and IL-23 have also been shown to have a role in the pathogenesis of CIA [10] and colitis [11,12]. These studies established a pathogenic role for Th17 cells in organ-specific autoimmune and chronic inflammatory diseases.…”