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Inflamm Bowel Dis. 2015 May;21(5):973-84. doi: 10.1097/MIB.0000000000000353.

Neutralizing IL-23 is superior to blocking IL-17 in suppressing intestinal inflammation in a spontaneous murine colitis model.

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*Immunity, Infection and Inflammation Program, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba, Australia; †School of Biomedical Sciences and School of Medicine, University of Queensland, Brisbane, Australia; ‡School of Biomolecular and Physical Sciences, Griffith University, Nathan, Australia; and §School of Human Life Sciences, University of Tasmania, Launceston, Australia.



IL-23/T(H)17 inflammatory responses are regarded as central to the pathogenesis of inflammatory bowel disease, but clinically IL-17A antibodies have shown low efficacy and increased infections in Crohn's disease. Hence, we decided to closely examine the role of the IL-23/T(H)17 axis in 3 models of colitis.


IL-17A(-/-) and IL-17Ra(-/-) T cells were transferred into Rag1 and RaW mice to assess the role of IL-17A-IL-17Ra signaling in T cells during colitis. In Winnie mice with spontaneous colitis due to an epithelial defect, we studied the progression of colitis in the absence of IL-17A and the efficacy of neutralizing antibodies against the IL-17A or IL-23p19 cytokines.


In transfer colitis models, IL-17A-deficient T cells failed to ameliorate disease, and IL-17Ra-deficient T cells were more colitogenic than wild-type T cells. In Winnie mice with an epithelial defect and spontaneous T(H)17-dominated inflammation, genetic deficiency of IL-17A did not suppress initiation of colitis but limited colitis progression. Furthermore, inhibition of IL-17A by monoclonal antibodies did not reduce colitis severity. In contrast, neutralizing IL-23 using an anti-p19 antibody significantly alleviated both emerging and established colitis, downregulating T(H)17 proinflammatory cytokine expression and diminishing neutrophil infiltration.


Our results support clinical studies showing that IL-17 neutralization is not therapeutic but that targeting IL-23 suppresses intestinal inflammation. Effects of IL-23 distinct from its effects on maturation of IL-17A-producing lymphocytes may underlie the protection from inflammatory bowel disease conveyed by hypomorphic IL-23 receptor polymorphisms and contribute to the efficacy of IL-23 neutralizing antibodies in inflammatory bowel disease.

[Indexed for MEDLINE]

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