IL-12 p40 monomer is different from other IL-12 family members to selectively inhibit IL-12Rβ1 internalization and suppress EAE

Susanta Mondal, Madhuchhanda Kundu, Malabendu Jana, Avik Roy, Suresh B. Rangasamy, Khushbu K. Modi, Jennillee Wallace, Yasmeen A. Albalawi, Roumen Balabanov, Kalipada Pahan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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 (p402). 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 p402in 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 p402did 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 p402-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 fromIL-12, IL-23, and p402inwhich it attenuates autoimmune signaling via suppression of IL-12Rβ1 internalization, which may be beneficial in patients with MS and other autoimmune disorders.

Original languageEnglish (US)
Pages (from-to)21557-21567
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number35
DOIs
StatePublished - Sep 1 2020

Keywords

  • EAE
  • IL-12 p40 monomer
  • IL-12Rβ1
  • Multiple sclerosis
  • Rheumatoid arthritis

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'IL-12 p40 monomer is different from other IL-12 family members to selectively inhibit IL-12Rβ1 internalization and suppress EAE'. Together they form a unique fingerprint.

Cite this