A novel cytokine consisting of the p40 and EBI3 subunits suppresses experimental autoimmune arthritis via reciprocal regulation of Th17 and Treg cells

• Published in: Cellular & molecular immunology 2022-01, Vol.19 (1), p.79-91
• Main Authors: Lee, Seon-Yeong, Moon, Su-Jin, Moon, Young-Mee, Seo, Hyeon-Beom, Ryu, Jun-Geol, Lee, A Ram, Lee, Chae Rim, Kim, Da-Som, Her, Yang-Mi, Choi, Jeong Won, Kwok, Seung-Ki, Park, Sung-Hwan, Cho, Mi-La
• Format: Article
• Language: English
• Subjects: 631/250/127; 631/250/38; Animals; Antibodies; Arthritis; Arthritis, Experimental; Autoimmune Diseases; Biomedical and Life Sciences; Biomedicine; CD25 antigen; CD4 antigen; Cell differentiation; Collagen; Cytokines; Cytokines - therapeutic use; Enzyme-linked immunosorbent assay; Fc receptors; Foxp3 protein; Gene expression; Helper cells; IL-1β; Immune response; Immunology; Immunoprecipitation; Immunoregulation; Inflammation; Interleukin 12; Interleukin 17; Interleukin 23; Interleukin 6; Interleukin-12 - chemistry; Interleukin-12 - metabolism; Lymphocytes T; Medical Microbiology; Mice; Microbiology; Minor Histocompatibility Antigens; Osteoclastogenesis; Proteins; Receptors, Cytokine - genetics; Receptors, Cytokine - therapeutic use; T-Lymphocytes, Regulatory; Th17 Cells; Tumor necrosis factor-α; Vaccine; Western blotting
• ISSN: 1672-7681; 2042-0226
• DOI: 10.1038/s41423-021-00798-2

Objective The interleukin (IL)-12 cytokine family is closely related to the development of T helper cells, which are responsible for autoimmune disease enhancement or suppression. IL-12 family members are generally heterodimers and share three α-subunits (p35, p19, and p28) and two β-subunits (p40 and EBI3). However, a β-sheet p40 homodimer has been shown to exist and antagonize IL-12 and IL-23 signaling 1 . Therefore, we assumed the existence of a p40-EBI3 heterodimer in nature and sought to investigate its role in immune regulation. Methods The presence of the p40-EBI3 heterodimer was confirmed by ELISA, immunoprecipitation, and western blotting. A p40-EBI3 vector and p40-EBI3-Fc protein were synthesized to confirm the immunological role of this protein in mice with collagen-induced arthritis (CIA). The anti-inflammatory effects of p40-EBI3 were analyzed with regard to clinical, histological, and immune cell-regulating features in mice with CIA. Results Clinical arthritis scores and the expression levels of proinflammatory cytokines (e.g., IL-17, IL-1β, IL-6, and TNF-α) were significantly attenuated in p40-EBI3-overexpressing and p40-EBI3-Fc-treated mice with CIA compared to vehicle-treated mice with CIA. Structural joint damage and vessel formation-related gene expression were also reduced by p40-EBI3 heterodimer treatment. In vitro, the p40-EBI3-Fc protein significantly suppressed the differentiation of Th17 cells and reciprocally induced CD4 + CD25 + Foxp3 + (regulatory T) cells. p40-EBI3 also inhibited osteoclast formation in a concentration-dependent manner. Conclusion In this study, p40-EBI3 ameliorated proinflammatory conditions both in vivo and in vitro. We propose that p40-EBI3 is a novel anti-inflammatory cytokine involved in suppressing the immune response through the expansion of Treg cells and suppression of Th17 cells and osteoclastogenesis.