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 cavitie s of BALB/c mice results in a chronic peritonitis associated with high tissue levels of interleukin 6 (IL-6), Here we show that increased pr ostaglandin E(2) (PGE(2)) synthesis causes induction of IL-6 and that expression of an inducible cyclooxggenase, Cox-2, may mediate this pro cess, Levels of both PGE(2) and IL-6 are elevated in inflammatory exud ates from pristane-treated mice compared with lavage samples from untr eated mice. The Cox-a gene is induced in the peritoneal macrophage fra ction isolated from the mice, A cause and effect relationship between increased macrophage PGE(2) and IL-6 production is shown in vitro, Whe n 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, Cotr eatment with 1 mu M indomethacin inhibits PGE(2) production by the cel ls and reduces the induction of IL-6 mRNA but has no effect on Cox-2 m RNA, consistent with the fact that the drug inhibits catalytic activit y of the cyclooxygenase but does not affect expression of the gene. Ad dition of exogenous PGE(2) to macrophages induces IL-6 protein and mRN A 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 earli er finding that indomethacin diminishes the elevation of IL-6 in prist ane-treated mice, the results show that PGE(2) can induce IL-6 product ion in vivo and implicate expression of the Cox-2 gene in the regulati on of this cytokine.