DIFFERENTIAL REGULATION OF INTERLEUKIN-6, MACROPHAGE INFLAMMATORY PROTEIN-1, AND JE/MCP-1 CYTOKINE EXPRESSION IN MACROPHAGE CELL-LINES

Activated macrophages produce a number of proinflammatory cytokines including IL-6, JE, MIP-1α and MIP-1β. The induction requirements for production of either IL-6 or the MIP-1 related inflammatory proteins (MIP-1α, MIP-1β, and JE) have been analyzed independently using fibroblasts, monocytes, or endothelial cells. However, little is known about the regulation of these cytokines in macrophages. Since activated macrophages produce prostaglandins (PGE2) which may participate in the autoregulation of cytokine production by stimulation of adenylate cyclase and the induction of cAMP-dependent signal pathways, we determined the effects of PGE on the production of IL-6 and MIP-1 -related proteins. Murine macrophage cell lines were incubated with PGE1, PGE2, cholera toxin, or dibutyryl cAMP in the presence or absence suboptimal doses of LPS. Pharmacologic agents alone did not induce IL-6 production but incubation of macrophages with combinations of adenylate cyclase stimulators and LPS or dcAMP and LPS led to the dosedependent enhancement of IL-6 secretion and mRNA expression. In contrast, PGE1 inhibits LPS-induced JE, MIP-1α, and MIP-1β mRNA expression and this inhibition is partially dependent on a cAMP-mediated pathway of signal transduction. In previous work we demonstrated that IFN-γ and PMA do not stimulate the production of IL-6 by macrophages. Here we show that incubation of macrophages with either IFN-γ or PMA induces the expression of JE, MIP-1α and MIP-1β mRNA expression. JE mRNA expression is much more responsive to the stimulatory effects of IFN-γ than are the MIP-1 genes. Finally, PGE inhibits PMA and IFN-γ-induced JE and MIP-1-related mRNA expression. © 1991.