The functional relevance of interleukin 6 (IL-6) in platelet-derived growth factor (PDGF)-induced cell growth was evaluated in cultures of human fibroblasts, vascular smooth muscle cells, and mesangial cells. The three isoforms of the PDGF--namely, PDGF-AA, -AB, and -BB--induced the expression of the IL-6 gene and proliferation of the nontransformed cells. PDGF-induced transcription, translation, and secretion of IL-6 were diminished in the presence of IL-6 antisense oligonucleotides. While neutralizing anti-IL-6 antibodies failed to affect the growth factor-dependent cell proliferation, IL-6 antisense oligonucleotides inhibited cell division. In addition, IL-6 antisense oligonucleotides abolished PDGF-induced transcription of the genes coding for the cell division cycle 2-related protein (CDC2) and proliferating cell nuclear antigen (PCNA), both of which are regulated in a cell cycle-dependent manner. It is concluded that PDGF-dependent proliferation of nontransformed cells involves the action of intracellular IL-6.