ACTIVATION OF THE ENDOTHELIUM BY IL-1-ALPHA AND GLUCOCORTICOIDS RESULTS IN MAJOR INCREASE OF COMPLEMENT C3 AND FACTOR-B PRODUCTION AND GENERATION OF C3A

Constitutive secretion of complement C3 and factor B by the endothelia l cell (EC) is lowered by therapeutic concentrations of glucocorticoid s such as hydrocortisone or dexamethasone, whereas regulatory protein factor H production is increased by these hormones. In contrast, the p roinflammatory cytokine IL-1 alpha has a stimulatory effect on C3 and factor B secretion by the endothelium and an inhibitory effect on fact or H secretion. In this study, we examined the combined effect of IL-1 alpha and glucocorticoids on C3 and factor B expression by the endoth elial cell. When dexamethasone or hydrocortisone were added to IL-1 al pha, significant potentialization of IL-1 alpha-induced stimulation of C3 and factor B production was observed, occurring at various concent rations of either stimuli. Dose-response experiments indicate that, in vitro, optimal concentrations are in the range of 10(-7) to 10(-5) M for dexamethasone and 50-200 U for IL-1 alpha. In contrast, dexamethas one counteracts, in an additive way, the inhibitory effect of IL-1 alp ha on regulatory complement protein factor H production by EC. Such a potentialization between glucocorticoids and IL-1 alpha was not observ ed for another marker of endothelial activation, IL-1 alpha-induced st imulation of coagulation tissue factor expression. The association of glucocorticoids and IL-1 alpha therefore appears to be a specific and major stimulus for the secretion of complement C3 and factor B, two ac ute-phase proteins, by the endothelium. As a result of the in vitro en dothelium stimulation by glucocorticoids and IL-1 alpha, C3a is genera ted in the vicinity of the endothelial cell. This study further sugges ts that complement activation, with its deleterious consequences, may result from the stimulation of endothelium in situations where high le vels of IL-1 alpha and endogenous glucocorticoids coexist, such as in septic shock.