REGULATION OF T-CELL-DEPENDENT AND T-CELL-INDEPENDENT IL-12 PRODUCTION BY THE 3 TH2-TYPE CYTOKINES IL-10, IL-6, AND IL-4

The production of IL-12 by macrophages/dendritic cells (M phi/DC) is m ediated either by a T cell-dependent pathway that is induced primarily by the interaction of CD40 ligand (CD40L) on activated T cells with C D40 on IL-12-producing cells or by a T cell-independent pathway that i s induced by bacteria or bacterial products and enhanced by interferon -gamma (IFN-gamma), In this study we investigated the ability of the T h2-type cytokines interleukin (IL) -10, IL-6, and IL-4 to modulate IL- 12 production in M phi/DC induced through the two pathways, IL-12 prod uction was induced in M phi/DC from normal mice by stimulation with th e combination of IFN-gamma plus lipopolysaccharide (LPS) or Staphyloco ccus aureus Cowan I (a model for the T cell-independent pathway) or by co-culture with Chinese hamster ovary (CHO) cells transfected with th e CD40L (a model for the T cell-dependent pathway), The effects of thr ee Th2-type cytokines on IL-12 production by M phi/DC through the two pathways were examined, IL-10 inhibited IL-12 production induced throu gh both pathways, although the inhibitory effect was more potent on th e (IFN-gamma + LPS)-induced pathway,IL-6 inhibited only (LPS + IFN-gam ma)-induced IL-12 production, The effect of IL-4 was particularly note worthy: this cytokine inhibited(LPS + IFN-gamma)-induced IL-12 product ion, whereas it potentiated the production of IL-12 induced by CD40L. Regulation of IL-12 protein production by IL-10 and IL-4 was found to correspond to the levels of mRNA accumulation for the p40 and p35 IL-1 2 genes, whereas the presence of IL-6 during stimulation decreased IL- 12 protein production without affecting steady-state mRNA levels, Thes e results indicate that IL-12 production in M phi/DC induced through a T cell-dependent or -independent pathway is positively or negatively regulated by particular cytokines at various control levels.