INTERACTION BETWEEN ONCOSTATIN-M, INTERLEUKIN-1 AND PROSTAGLANDIN E(2) IN INDUCTION OF IL-6 EXPRESSION IN HUMAN FIBROBLASTS

The role of Oncostatin M (OM), a monocyte/macrophage and T-cell product, in regulating IL-6 expression in fibroblasts of lung or synovial origin was examined in vitro. Although by itself OM had a minimal effect on enhancing IL-6 production by fibroblasts, in combination with IL-1α or PGE2, OM addition resulted in a dose-dependent synergistic enhancement of IL-6 production. This synergistic effect with either IL-1α (5 ng/ml) or PGE2 (10-7 M) was clearly evident at concentrations of OM of 10, 20 or 50 ng/ml. Levels of IL-6 resulting from OM and IL-1α stimulation could be reduced by indomethacin (10-6 M) and restored again by also adding PGE2. Northern blots probed for IL-6 mRNA showed cooperative enhancement of steady state levels at 18 hours of stimulation by OM and IL-1α, or OM and PGE2. Probing for mRNA of the metalloproteinase inhibitor TIMP-1 showed that stimulation by OM, IL-1α or PGE2 enhanced TIMP-1 levels. However, OM (alone) or PGE2 or both combined did not elevate the metalloproteinase stromelysin-1 mRNA signals. Analysis utilizing a rat IL-6 promoter-luciferase reporter gene construct showed that OM stimulation resulted in activation of transcription that synergistically enhanced IL-1-induced levels of reporter gene expression. These results show that although OM has minor effects on IL-6 production alone, the combination of OM and other mediators result in markedly enhanced IL-6 production by fibroblasts in vitro. © 1994 Academic Press Limited.