Interleukin-12 (IL-12) plays a central role in the immune system by driving the immune response towards T helper 1 (Th1) type responses characterized by high IFN-gamma and low IL-4 production. In this study we investigated whether retinoid-mediated inhibition of interleukin-12 production in mouse macrophages could regulate cytokine profile of antigen (Ag)-primed CD4(+) Th cells. Pretreatment with retinoids (9-cis-RA, all-trans-RA, TTNPB) significantly inhibited IL-12 production by mouse macrophages stimulated with lipopolysaccharide (LPS) or heated-killed Listeria monocytogenes (HKL). Retinoid-pretreated macrophages reduced their ability to induce IFN-gamma and increased the ability to induce IL-4 in Ag-primed CD4(+) T cells. Addition of recombinant IL-12 to cultures of retinoid-pretreated macrophages and CD4(+) T cells restored IFN-gamma production in CD4(+) T cells. The in vivo administration of 9-cis-RA resulted in the inhibition of IL-12 production by macrophages stimulated in vitro with either LPS or HKL, leading to the inhibition of Th1 cytokine profile (decreased IFN-gamma and increased IL-4 production) in CD4(+) T cells. These findings may explain some known effects of retinoids including the inhibition of encephalitogenicity, and point to a possible therapeutic use of retinoids in the Th1-mediated immune diseases such as autoimmune diseases.