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

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 p402 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 p402 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 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 from IL-12, IL-23, and p402 in which it attenuates autoimmune signaling via suppression of IL-12Rβ1 internalization, which may be beneficial in patients with MS and other autoimmune disorders.

Regression of Triple-Negative Breast Cancer in a Patient-Derived Xenograft Mouse Model by Monoclonal Antibodies against IL-12 p40 Monomer

“…IL-12 family of cytokines has four different members including p40 monomer (p40), p40 homodimer (p40 2 ), IL-12 (p40:p35), and IL-23 (p40:p19) [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. Recently we have delineated that p40 is different from other IL-12 family members to selectively inhibit IL-12Rβ1 internalization and suppress autoimmune demyelination [ 5 ].…”

“…IL-12 family of cytokines has four different members including p40 monomer (p40), p40 homodimer (p40 2 ), IL-12 (p40:p35), and IL-23 (p40:p19) [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. Recently we have delineated that p40 is different from other IL-12 family members to selectively inhibit IL-12Rβ1 internalization and suppress autoimmune demyelination [ 5 ]. We have also seen that certain cancer cells stave off their death with the help from p40 and that selective depletion of p40 by a functional blocking mAb leads to regression of prostate tumor in mice [ 4 ].…”

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