Regulation of BSF-2/IL-6 production in peripheral mononuclear cells (MNC) was studied. BSF-2 mRNA expression in mitogen-stimulated MNC showed a biphasic response, the first peak around 4 h and the second peak around 48 h. This was caused by different kinetics of BSF-2 mRNA expression in distinct subpopulations of MNC; M phi expressed BSF-2 mRNA at 5 h in the absence of any stimulation, and mitogen-stimulated T cells and B cells expressed BSF-2 mRNA 48 h after stimulation. Immunohistochemical staining of the cells with anti-BSF-2 antibody demonstrated that macrophages, T cells and B cells could produce BSF-2. T cells in peripheral MNC produced BSF-2 in the presence of M phi. The requirement of macrophage for BSF-2 production in T cells could be replaced by TPA but not by IL-1 or BSF-2.