Elevated interleukin 6 is induced by prostaglandin E(2) in a murine model of inflammation: Possible role of cyclooxygenase-2

Injection of mineral oils such as pristane into the peritoneal cavities of BALB/c mice results in a chronic peritonitis associated with high tissue levels of interleukin 6 (IL-6), Here we show that increased prostaglandin E(2) (PGE(2)) synthesis causes induction of IL-6 and that expression of an inducible cyclooxggenase, Cox-2, may mediate this process, Levels of both PGE(2) and IL-6 are elevated in inflammatory exudates from pristane-treated mice compared with lavage samples from untreated mice. The Cox-a gene is induced in the peritoneal macrophage fraction isolated from the mice, A cause and effect relationship between increased macrophage PGE(2) and IL-6 production is shown in vitro, When peritoneal macrophages are activated with an inflammatory stimulus (polymerized albumin), the Cox-2 gene is induced and secretion of PGE(2) and IL-6 increases, with elevated PGE(2) appearing before IL-6, Cotreatment with 1 mu M indomethacin inhibits PGE(2) production by the cells and reduces the induction of IL-6 mRNA but has no effect on Cox-2 mRNA, consistent with the fact that the drug inhibits catalytic activity of the cyclooxygenase but does not affect expression of the gene. Addition of exogenous PGE(2) to macrophages induces IL-6 protein and mRNA synthesis, indicating that the eicosanoid stimulates IL-6 production at the level of gene expression, PGE(2)-stimulated IL-6 production is unaffected by addition of indomethacin. Taken together with the earlier finding that indomethacin diminishes the elevation of IL-6 in pristane-treated mice, the results show that PGE(2) can induce IL-6 production in vivo and implicate expression of the Cox-2 gene in the regulation of this cytokine.