Abstract
Interleukin 35 (IL-35) is a heterodimeric cytokine composed of IL-12p35 and Ebi3 subunits. IL-35 suppresses autoimmune diseases while preventing host defense to infection and promoting tumor growth and metastasis by converting resting B and T cells into IL-10-producing and IL-35-producing regulatory B (Breg) and T (Treg) cells. Despite sharing the IL-12p35 subunit, IL-12 (IL-12p35/IL-12p40) promotes inflammatory responses whereas IL-35 (IL-12p35/Ebi3) induces regulatory responses, suggesting that IL-12p35 may have unknown intrinsic immune-regulatory functions regulated by its heterodimeric partner. Here we show that the IL-12p35 subunit has immunoregulatory functions hitherto attributed to IL-35. IL-12p35 suppresses lymphocyte proliferation, induces expansion of IL-10-expressing and IL-35-expressing B cells and ameliorates autoimmune uveitis in mice by antagonizing pathogenic Th17 responses. Recapitulation of essential immunosuppressive activities of IL-35 indicates that IL-12p35 may be utilized for in vivo expansion of Breg cells and autologous Breg cell immunotherapy. Furthermore, our uveitis data suggest that intrinsic immunoregulatory activities of other single chain IL-12 subunits might be exploited to treat other autoimmune diseases.
Highlights
Interleukin 35 (IL-35) is a heterodimeric cytokine composed of IL-12p35 and Ebi[3] subunits
We showed that IL-12p40-deficient mice are resistant to experimental autoimmune uveitis (EAU), suggesting that endogenous or interleukin 12 (IL-12) or IL-23 is required for induction and progression of EAU12
IL-35 is composed of Ebi[3], a β-chain subunit encoded by the Epstein−Barr virus (EBV)-induced gene 3 (Ebi[3], known as IL27b), and the IL-12p35 α subunit encoded by IL12a21, 22, 24
Summary
Interleukin 35 (IL-35) is a heterodimeric cytokine composed of IL-12p35 and Ebi[3] subunits. Despite sharing the IL-12p35 subunit, IL-12 (IL-12p35/IL-12p40) promotes inflammatory responses whereas IL-35 (IL-12p35/Ebi3) induces regulatory responses, suggesting that IL-12p35 may have unknown intrinsic immune-regulatory functions regulated by its heterodimeric partner. Our uveitis data suggest that intrinsic immunoregulatory activities of other single chain IL-12 subunits might be exploited to treat other autoimmune diseases. Inflammatory stimuli induce microglial cells of the neuroretina to produce IL-27, and this immune-suppressive IL-12 member has been shown to inhibit Th17-mediated ocular inflammation and contribute to the a Fractions: 15 16 17 18 19 20 21 22 23 MW kDa. IL-35 is the other anti-inflammatory member of the IL-12 family of cytokines[21,22,23]. Our data indicate that IL-12p35, while not readily detectable in vivo in the steady-state, possesses at least some of the immune-regulatory properties of the heterodimeric IL-35 cytokine and when used therapeutically it is able to control autoimmune disease affecting the neuroretina
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call