THE ROLE OF INTERLEUKIN-1 AND TUMOR NECROSIS FACTOR-ALPHA IN HUMAN MULTIPLE-MYELOMA

This study investigates the capacity of interleukin‐1α (IL‐1α), interleukin‐1β (IL‐1β) and tumour necrosis factor‐α (TNF‐α) to induce interleukin‐6 (IL‐6) production in freshly isolated myeloma cells (MC) and bone marrow‐derived stromal cells (MSC). Recombinant human (rh) IL‐1α, IL‐1β and TNF‐α 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‐1α, IL‐1β and TNF‐α with their respective antibodies inactivated the ability of recombinant cytokines to stimulate the release of IL‐6 from myeloma cells. IL‐1α, IL‐1β and TNF‐α 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‐lα, IL‐1β and TNF‐α 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‐α may play an important role in the pathogenesis of human multiple myeloma. Copyright © 1990, Wiley Blackwell. All rights reserved