COMPARATIVE EFFECTS OF INTERLEUKIN-1 AND TUMOR-NECROSIS-FACTOR-ALPHA ON COLLAGEN PRODUCTION AND CORRESPONDING PROCOLLAGEN MESSENGER-RNA LEVELS IN HUMAN DERMAL FIBROBLASTS

The effects of recombinant human Interleukin-1-alpha (IL-1-alpha), Interleukin-1-beta (IL-1-beta), and Tumor Necrosis Factor-alpha (TNF-alpha) on collagen biosynthesis were studied in vitro using dermal fibroblast cultures. Both forms of IL-1 and TNF-alpha induced a dose-dependent inhibition of both types of I and III collagen synthesis, as measured by radioimmunoassay, gel electrophoresis, or collagenase-sensitive material. This effect was accompanied by a significant release of prostaglandin E2 into the culture medium. However, indomethacin, a potent inhibitor of prostaglandin synthesis, could not prevent the inhibitory effect of the three cytokines on collagen synthesis. Measurement of type I and type III procollagen mRNA levels in IL-1 treated cells revealed that both IL-1-alpha and IL-1-beta were potent enhancers of procollagen gene expression at pretranslational level. On the other hand, TNF-alpha was found to reduce the steady-state levels of type I and III procollagen mRNA in a dose-dependent manner. Quantitation of IL-1-beta and TNF-alpha transcripts following TNf-alpha treatment of fibroblasts indicated that this cytokine can induce IL-1-beta gene expression in these cells. By contrast, TNF-alpha remained at a constant level after TNF-alpha exposure. Quantitation of IL-1-beta and TNF-alpha transcripts following TNF-alpha treatment of fibroblasts indicated that this cytokine can induce IL-1-beta gene expression in these cells. By contrast, TNF-alpha mRNA remained at at constant level after TNF-alpha exposure. These data suggest that IL-1 and TNF-alpha, two cytokines that share several biologic activities, modulate collagen disposition in dermal fibroblasts by mechanisms that are clearly different: TNF-alpha appears to act at a transcriptional level to inhibit collagen synthesis, whereas IL-1 inhibitory action involves important translational regulation, still unknown, that counterbalances its stimulatory effect on procollagen mRNA levels. Moreover, our data suggest the existence of local fibroblastic cytokine production that may be involved in the modulation of extracellular matrix disposition.