Interleukin-1 and transforming growth factor-alpha: synergistic stimulation of metalloproteinases, PGE2, and proliferation in human fibroblasts.

Wound healing and other inflammatory processes are driven by a complex series of interactions among cells, the extracellular matrix, and secreted products of various cell types. Cytokines, such as interleukin-1 and transforming growth factor-alpha, are present at wound sites and contribute to the proinflammatory milieu of these sites. In the present study, we have investigated the effect of these cytokines, individually and in concert, on fibroblast expression of matrix metalloproteinases, which contribute to extracellular matrix remodeling, and of prostaglandin E2, which alters vascular tone and permeability. The metalloproteinases, procollagenase (matrix metalloproteinase-1) and prostromelysin (matrix metalloproteinase-3), are induced by exposure of dermal fibroblasts to interleukin-1, not stimulated by transforming growth factor-alpha, but are synergistically induced by the combination of cytokines. The 92-kDa type IV procollagenase (matrix metalloproteinase-9, progelatinase B), is also stimulated in synergistic fashion. Prostaglandin E2 is induced in rheumatoid synovial fibroblasts by interleukin-1 beta, not altered by transforming growth factor-alpha, and is synergistically released by the combination of the two cytokines. Fibroblast proliferation, which is also a component of normal wound healing, is also synergistically stimulated by the action of the two cytokines in concert. These results indicate that interleukin-1 beta and transforming growth factor-alpha synergize to elicit a number of phenotypic responses in fibroblasts which are relevant to normal wound healing and chronic inflammation.