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

journal contribution
posted on 2023-05-18, 09:06 authored by Wang, R, Hasnain, SZ, Tong, H, Das, I, Che-Hao Chen, A, Oancea, I, Proctor, M, Florin, TH, Rajaraman Eri, McGukin, MA

Background: IL-23/TH17 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/TH17 axis in 3 models of colitis.

Methods: 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.

Results: 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 TH17-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 TH17 proinflammatory cytokine expression and diminishing neutrophil infiltration.

Conclusions: 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.


National Health & Medical Research Council


Publication title

Inflammatory Bowel Diseases










School of Nursing


Lippincott Williams & Wilkins

Place of publication

530 Walnut St, Philadelphia, USA, Pa, 19106-3621

Rights statement

Copyright 2015 Crohn’s & Colitis Foundation of America, Inc.

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Socio-economic Objectives

Clinical health not elsewhere classified

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