Cytokines and Growth Factors Positively and Negatively Regulate Interstitial Collagen Gene Expression in Human Vascular Smooth Muscle Cells

Abstract

Human atheromas accumulate extracellular matrix proteins such as collagen types I and III. We tested whether cytokines or growth factors produced by cells found in human atherosclerotic plaques alter collagen gene expression in vascular smooth muscle cells (VSMCs), which produce the blood vessel matrix. Interleukin-1 (IL-1, 1-10 ng/ml) modestly increased the synthesis of collagens I and III (measured by tritiated proline incorporation into specific electrophoretic bands), whereas transforming growth factor-\(\beta\) (TGF-\(\beta\)) or platelet-derived growth factor (PDGF) markedly stimulated production of these interstitial collagens. Interferon \(\gamma\) (IFN-\(\gamma\)), a product of activated T cells found in atheromas, selectively alters several VSMC functions. For example, this cytokine reduces growth of VSMCs, decreases alpha-actin gene expression, and induces VSMC expression of class II histocompatibility antigens. We report here that IFN-\(\gamma\) also inhibits basal as well as IL-1-, PDGF-, or TGF-\(\beta\)-stimulated collagen I and III synthesis by human VSMCs. TGF-\(\beta\), the most potent stimulator of collagen synthesis studied here, raised the level of collagen III mRNA in VSMCs 4.8-fold (determined by densitometry of Northern blots), whereas exposure to both TGF-\(\beta\) and IFN-\(\gamma\) reduced this mRNA to 0.5 of basal level. Locally produced cytokines and growth factors may thus modify matrix accumulation during atherogenesis by stimulating or suppressing expression of interstitial collagen mRNA and protein by VSMCs.