Interleukin-6 production by endotoxin-stimulated kupffer cells is regulated by prostaglandin E 2

Abstract

Although its impact on the acute phase response is clear, little is known regarding the regulation of interleukin-6 (hepatocyte-stimulating factor) production. We evaluated its relationship with the potent immunosuppressive eicosanoid PGE 2 in endotoxin (LPS)-stimulated Kupffer cells (KC). KC were harvested from collagenasedigested Wistar-Furth rat livers and purified (>95% by phagocytosis) by adherence. Following overnight culture with or without the cyclooxygenase inhibitor indomethacin (10 μ M), 5 × 10 5 KC were repleted with fresh media with or without 2.5 μg/ml LPS. Supernatant IL-6 levels (ng/ml) were measured with the B9.9 hybridoma proliferative bioassay, and PGE 2 levels (ng/ml) by radioimmunoassay. Negligible supernatant IL-6 and PGE 2 were measured at all culture intervals in unstimulated KC or those cultured with the LPS-inhibitor polymyxin-B (10 μg/ml). With LPS, KC IL-6 production increased in parallel with PGE 2 for 24 hr before decreasing as PGE 2 continued to rise. When indomethacin treatment blocked KC PGE 2 production, IL-6 levels significantly increased. We conclude that PGE 2 produced by activated Kupffer cells appears to down-regulate IL-6 secretion. Autocrine effects by PGE 2 may locally regulate the hepatic acute phase response by limiting the KC-derived IL-6 available to act on neighboring hepatocytes.