Differential regulation of IL 6, IL 1 A, IL 1 beta and TNF alpha production in LPS-stimulated human monocytes: role of cyclic AMP

Abstract

Interleukin 6 (IL 6), IL 1 alpha, IL beta and tumor necrosis factor (TNF) alpha are four cytokines induced in monocytes by lipopolysaccharide (LPS); however, it is unclear whether the mechanisms which control their production are similar. In this study, we report the effects of prostaglandin E2 (PGE2), and two other cAMP-elevating agents, dibutyryl cAMP and 3-isobutyl-1-methyl-xanthine, on the in vitro LPS-induced production of IL 6, IL 1 alpha, IL 1 beta and TNF alpha by human monocytes. The production of these four cytokines was found to be selectively regulated in monocytes, by increases in intracellular cAMP levels. In effect, such agents enhanced, in a dose-dependent manner, both extracellular and cell-associated IL 6 production by LPS-stimulated monocytes. In contrast, it was confirmed, using the same samples, that these cAMP-elevating agents inhibit both extracellular and cell-associated TNF alpha production in a dose-dependent manner. IL 1 alpha and IL 1 beta production, measured by means of specific immunoreactive assays, were not significantly modified. Kinetic analysis showed that the potentiating effect of cAMP on IL 6 production, along with its inhibiting effect on TNF alpha production, could be seen as early as 1 hr after LPS stimulation. These results demonstrate that IL 6, TNF alpha, IL 1 alpha and IL 1 beta production can be differently modulated by an agent, PGE2, which is produced simultaneously by LPS-stimulated monocytes. Such differential autocrine modulation may play an important role in the regulation of the production of cytokines participating in immune and inflammatory responses.