文章基本信息

标题：IL-12 p40 monomer is different from other IL-12 family members to selectively inhibit IL-12Rβ1 internalization and suppress EAE
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作者：Susanta Mondal ; Madhuchhanda Kundu ; Malabendu Jana 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2020
卷号：117
期号：35
页码：21557-21567
DOI：10.1073/pnas.2000653117
出版社：The National Academy of Sciences of the United States of America
摘要：Multiple sclerosis (MS) is the most common human demyelinating disease of the central nervous system. The IL-12 family of cytokines has four members, which are IL-12 (p40:p35), IL-23 (p40:p19), the p40 monomer (p40), and the p40 homodimer (p40 2 ). Since all four members contain p40 in different forms, it is important to use a specific monoclonal antibody (mAb) to characterize these molecules. Here, by using such mAbs, we describe selective loss of p40 in serum of MS patients as compared to healthy controls. Similarly, we also observed decrease in p40 and increase in IL-12, IL-23, and p40 2 in serum of mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS, as compared to control mice. Interestingly, weekly supplementation of mouse and human recombinant p40 ameliorated clinical symptoms and disease progression of EAE. On the other hand, IL-12, IL-23, and p40 2 did not exhibit such inhibitory effect. In addition to EAE, p40 also suppressed collagen-induced arthritis in mice. Using IL-12Rβ1 −/− , IL-12Rβ2 −/− , and IL-12Rβ1 /− /IL-12Rβ2 −/− mice, we observed that p40 required IL-12Rβ1, but not IL-12Rβ2, to suppress EAE. Interestingly, p40 arrested IL-12–, IL-23–, or p40 2 -mediated internalization of IL-12Rβ1, but neither IL-12Rβ2 nor IL-23R, protected regulatory T cells, and suppressed Th1 and Th17 biasness. These studies identify p40 as an anti-autoimmune cytokine with a biological role different from IL-12, IL-23, and p40 2 in which it attenuates autoimmune signaling via suppression of IL-12Rβ1 internalization, which may be beneficial in patients with MS and other autoimmune disorders.
关键词：IL-12 p40 monomer ; multiple sclerosis ; rheumatoid arthritis ; EAE ; IL-12Rβ1