IL-12p35 promotes antibody-induced joint inflammation by activating NKT cells and suppressing TGF-β

The functional role of IL-12 in rheumatoid arthritis is controversial. Moreover, whether IL-12 contributes to regulation of Ab-induced joint inflammation remains unclear. To address these issues, we explored the functional roles of IL-12 in Ab-induced arthritis using the K/BxN serum transfer model. IL-12p35^-/- and IL-12Rβ₂^-/- mice were resistant to the development of arthritis. Injection of K/BxN serum into IL-12p40-yellow fluorescence protein reporter (yet40) mice induced CD11b ⁺ cells, CD11c⁺ cells, and Gr-1⁺ granulocytes to produce IL-12p40 in the joints. The levels of IFN-γ, IL-4, and IL-6 production were lower in joint tissues of IL-12p35^-/- and IL-12Rβ₂^-/- mice than in B6 mice, whereas levels of TGF-β expression were higher. Administering IL-12p35^-/- mice rIL-12 or IFN-γ restored joint inflammation and suppressed TGF-β production in joint tissues. Moreover, administering neutralizing anti-TGF-β mAb enhanced joint inflammation. Among the immune cells that infiltrated joint tissues during Ab-induced arthritis, NKT cells expressed IL-12β₂ receptors. Furthermore, the adoptive transfer of splenocytes from B6 or Gr-1⁺ granulocyte-depleted mice restored joint inflammation in IL-12Rβ₂^-/- mice as much as in B6 mice, whereas splenocytes from Jα18^-/- mice did not. These findings indicate that signals via IL-12β₂ receptors on NKT cells play a critical role in the development of Ab-induced arthritis. The IL-12p35/IFN-γ axis promotes Ab-induced joint inflammation by activating NKT cells and suppressing TGF-β, which may provide novel information for the development of new therapeutic strategies for the inhibition of rheumatoid arthritis.