STIMULATION OF COLLAGEN AND GLYCOSAMINOGLYCAN PRODUCTION IN CULTURED HUMAN ADULT DERMAL FIBROBLASTS BY RECOMBINANT HUMAN INTERLEUKIN-6

Interleukin (IL) 6 is a pleiotropic cytokine synthesized by fibroblasts in response to many stimuli, including IL-1-beta. To evaluate the possibility that previously observed stimulation of fibroblast biosynthetic functions by IL-1-beta may be mediated by autocrine IL-6, we investigated the effect of recombinant human (rh) IL-6 on the connective tissue-related biosynthetic functions of three lines of cultured human adult dermal fibroblasts. We found that rhIL-6 mimicked some of the activities of IL-1-beta, as 24-96-h treatment of confluent fibroblast cultures with rhIL-6 caused concentration (10 to 1000 ng/ml)-dependent increases in the production of collagen and the glycosaminoglycans (GAG), hyaluronic acid and chondroitin-4/6-sulfates, but had little effect on fibronectin or total protein production. Although the effective stimulating concentrations of IL-6 were within the range (almost-equal-to 100 ng/ml) we found produced by rhIL-1-beta-treated fibroblast cultures, rhIL-1-beta at 0.2-1.0 ng/ml induced significantly greater amounts of collagen and GAG than the maximum effective concentrations of IL-6. Moreover, an anti-rhIL-6 antibody, which effectively neutralized the fibroblast-stimulating activities of rhIL-6, only fractionally blocked the fibroblast-stimulating actions of rhIL-1-beta, suggesting autocrine IL-6 only partially mediates the effects of IL-1-beta on fibroblasts. Conversely, the fibroblast-stimulating effects of rhIL-6 are unlikely due to autocrine IL-1-beta, as an anti-rhIL-1-beta-antibody had only minimal inhibitory action on rhIL-6-treated fibroblast cultures. Overall these results suggest that IL-6 could function as a paracrine/autocrine regulator of dermal fibrotic repair.