Regulation of transforming growth factor-β production by interleukin-12

The induction of peripheral tolerance following oral antigen administration in several autoimmune disease and conventional animal models correlates with the production of transforming growth factor-β (TGF-β) and T helper type 2 (Th2) cytokines. The factors regulating TGF-β production and its relation to the Th2 response, however, have not been defined. We demonstrate that the systemic administration of antibodies to interleukin (IL)-12 to ovalbumin (OVA)-T cell receptor (TCR) transgenic mice fed high doses of OVA, followed by systemic OVA challenge, substantially enhances TGF-β, but not IL-4 production by peripheral T cells. Furthermore, we demonstrate in an in vitro T cell differentiation model that naive (CD4⁺/Mel-14^hi) OVA-TCR-T cells stimulated with OVA-pulsed dendritic cells (DC) produce four-to fivefold higher amounts of TGF-β when cultured with anti-IL-12 or anti-interferon-γ (IFN-γ). In this in vitro system, IL-4 was not required for TGF-β production by T cells; however, it appeared to enhance levels of TGF-β by promoting the growth of TGF-β-producing cells. Our findings demonstrate that IL-12 and IFN-γ are important negative regulators of TGF-β production both in vivo and in vitro, and that their modulation may be of benefit for the treatment of autoimmune disorders.