The Mechanism of Glucocorticoid Effects in Fibroblasts

Abstract

In vivo, the glucocorticoid steroids inhibit fibroblast growth and the production of specific cell products such as collagen and mucopolysaccharide. Depending on the source of the fibroblasts and their growth conditions, several responses can be observed in cultured cells; the proliferation of L cells is inhibited, the growth of synovial fibroblasts is usually stimulated, and some cultured fibroblasts do not respond. The inhibition of L cell growth is preceded by alterations in the rates of hexose and amino acid transport. As in other cell types, there is evidence that the effects of glucocorticoids in fibroblasts are mediated via the induction of new protein synthesis. The specific induced proteins responsible for inhibiting the growth of mouse L929 fibroblasts (or any other cell type) have not been identified. It is possible that glucocorticoids induce the synthesis of a few proteins that, by virtue of their ability to modify (either during or after translation) other proteins involved in several key cellular events, are able to compromise multiple systems and produce growth inhibition. Glucocorticoid-mediated alteration of protein phosphorylation could account for the pleiotropic nature of the hormone effect. To cause a glucocorticoid-specific response in the cell, these hormones must first bind to a cellular receptor. A significant amount of evidence suggests (a) that glucocorticoid receptors may undergo an energy-dependent cycling in the cell and (b) that a single receptor may be able to participate several times in the process of steroid binding and gene activation. Maximal physiological response to, and consequently the clinical response achieved with, a glucocorticoid is usually a function of the extent to which the hormone can be bound in a specific manner. Investigators have proposed that the specific glucocorticoid-binding capacity of a cell is determined by a phosphorylation-dephosphorylation mechanism.