Tumor necrosis factor interacts with interleukin-1 and interferons to inhibit fibroblast proliferation via fibroblast prostaglandin-dependent and -independent mechanisms.
Mononuclear cells are important regulators of fibroblast function. However, the soluble factors mediating these effects and the importance of intercytokine interactions in these regulating events remain poorly understood. We analyzed the effect of recombinant (r) interleukin-1-alpha (IL-1), tumor necrosis factor (TNF), and gamma, alpha, and beta 1 interferons (IFN), alone and in combination, on the proliferation of normal human lung fibroblasts. rIL-1 and rTNF weakly stimulated and the rIFNs inhibited fibroblast proliferation. Importantly, when rTNF was combined with rIL-1 or rIFN, synergistic inhibition of fibroblast proliferation was noted. The inhibition caused by rIFN-gamma plus rTNF was largely independent of fibroblast prostaglandin (PG) production because fibroblast PG levels were unaltered in the presence of these cytokines and blocking fibroblast PG production did not alter their inhibitory effect. In contrast, the inhibition caused by rIL-1 plus rTNF appeared to be at least partially mediated by fibroblast PG production because these cytokines acted synergistically to stimulate fibroblast PG production and blocking fibroblast PG production reversed the inhibition that they caused. These studies demonstrate that TNF can interact with IL-1 or IFN to inhibit the proliferation of normal diploid fibroblasts and that the inhibitory effects of these cytokine combinations are mediated by different mechanisms.
Elias
J A
JA
Department of Internal Medicine, Hospital of the University of Pennsylvania, Philadelphia 19104-4283.
D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004347:Drug Interactions; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007372:Interferons / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology*; D008168:Lung / Q000166:cytology / Q000187:drug effects*; D011453:Prostaglandins / Q000032:analysis / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D007375:Interleukin-1; D011453:Prostaglandins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007372:Interferons