Regulatory mechanisms underlying IL-12 production and the control of immune responses

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IL-12 secreted by macrophages (Mphi) is a critical cytokine for the induction of Th1 cells responsible for cellular immunity. Here we investigated mechanisms underlying the regulation of IL-12 production. 1. The non-MHC linked strain difference in the T-cell independent IL-12 production by murine splenic Mphi to LPS plus IFN-gamma stimulation was closely related with simultaneous production of IL-10 capable of inhibiting IL-12 synthesis. 2. In contrast to splenic Mphi, peritoneal Mphi failed to induce IL-12 upon stimulation with LPS + IFN-gamma or SAC + IFN-gamma due to high production of IL-10 and PGE2.3. Peritoneal Mphi from mice given complete Freund's adjuvant (CFA) acquired the ability to produce IL-12 to the stimulation. Interestingly, levels of IL-10 and PGE2 were markedly reduced in such CFA-treated peritoneal Mphi. 4. Analyzes of cell surface antigens by flow cytometry revealed that the expression of STK (stem cell-derived tyrosine kinase, a member of the hepatocyte growth factor receptor family) on normal peritoneal Mphi was remarkably decreased after CFA-treatment. This implies the association of IL-12-producing ability with downregulation of STK as well as IL-10 and PGE2.5. High IL-12 production was induced even by untreated peritoneal Mphi from SJL/J mice exhibing a high incidence of experimental autoimmune encephalomyelitis mediated by Th1 cells and from MRL/Ipr mice spontaneously developing systemic autoimmune disease. 6. The presence of B cells constitutively expressing CD40 dramatically inhibited the T-cell dependent IL-12 induction to Con A or anti-CD3epsilon mAb stimulation, in which T-Mphi cell interaction through CD40L-CD40 molecules was required. This inhibition seemed to be caused by a competitive blocking of T-Mphi cell interaction by B cells incapable of producing IL-12.