Mechanism of inhibition of LPS-induced IL-12p40 production by IL-10 and TGF-β in ANA-1 cells

IL-12, a macrophage-derived proinflammatory cytokine, consists of two polypeptide subunits (p40 and p35) encoded by two separate genes. The p35 subunit is constitutively expressed, whereas the p40 subunit is induced after activation, The bioactive interleukin-12 (IL-12; p70) influences the development of Th1 responses and is a potent activator of natural killer (NK) and T cells. In contrast to IL-12, transforming growth factor beta (TGF-beta) and IL-10 inhibit production of proinflammatory cytokines, including IL-12, and attenuate Th1-mediated immune response. We have examined the molecular mechanisms by which TGF-beta and IL-10 inhibit production of the IL-12p40 subunit in LPS-stimulated murine macrophage cell line, We show that both IL-10 and TGF-beta suppress IL-12p40 production by inhibiting the transcription of IL-12p40 gene. At equal concentrations, IL-10 was more potent than TGF-beta in inhibiting IL-12p40 gene transcription. TGF-beta also reduces the stability of IL-12p40 mRNA, accounting thereby to an additional mechanism of inhibition of IL-12 production.