This study investigates the capacity of interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha) to induce interleukin-6 (IL-6) production in freshly isolated myeloma cells (MC) and bone marrow-derived stromal cells (MSC). Recombinant human (rh) IL-1 alpha, IL-1 beta and TNF-alpha augmented production of IL-6 in human MC. IL-6 was determined on a factor-dependent Cess cell line. This activity was completely abrogated by anti-IL-6 antibodies. Prior incubation of IL-1 alpha, IL-1 beta and TNF-alpha with their respective antibodies inactivated the ability of recombinant cytokines to stimulate the release of IL-6 from myeloma cells. IL-1 alpha, IL-1 beta and TNF-alpha enhanced 3H-TdR uptake in myeloma cells through IL-6, as antibodies to IL-6 completely abolished the DNA synthesis induced by culture supernatants of MC exposed to these cytokines. rhIL-6 reversed the inhibitory action of anti-IL-6 antibodies and reinduced DNA synthesis in MC. Next we found that IL-1 alpha, IL-1 beta and TNF-alpha induced MSC to produce IL-6. In contrast, supernatants of unstimulated MSC did not contain detectable IL-6 biologic activity. Further data demonstrated that human MC were able to induce IL-6 production in MSC. The stimulatory activities of MC appeared to be mediated through endogenously released IL-1, as the addition of antibodies towards IL-1 at the initiation of cocultures completely abrogated the IL-6 production. We conclude from our data that IL-1 and TNF-alpha may play an important role in the pathogenesis of human multiple myeloma.