Interleukin-6 production by endotoxin-stimulated Kupffer cells is regulated by prostaglandin E2.
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 PGE2 in endotoxin (LPS)-stimulated Kupffer cells (KC). KC were harvested from collagenase-digested Wistar-Furth rat livers and purified (greater than 95% by phagocytosis) by adherence. Following overnight culture with or without the cyclooxygenase inhibitor indomethacin (10 microM), 5 X 10(5) KC were repleted with fresh media with or without 2.5 micrograms/ml LPS. Supernatant IL-6 levels (ng/ml) were measured with the B9.9 hybridoma proliferative bioassay, and PGE2 levels (ng/ml) by radioimmunoassay. Negligible supernatant IL-6 and PGE2 were measured at all culture intervals in unstimulated KC or those cultured with the LPS-inhibitor polymyxin-B (10 micrograms/ml). With LPS, KC IL-6 production increased in parallel with PGE2 for 24 hr before decreasing as PGE2 continued to rise. When indomethacin treatment blocked KC PGE2 production, IL-6 levels significantly increased. We conclude that PGE2 produced by activated Kupffer cells appears to down-regulate IL-6 secretion. Autocrine effects by PGE2 may locally regulate the hepatic acute phase response by limiting the KC-derived IL-6 available to act on neighboring hepatocytes.
Callery
M P
MP
Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri 63110.
Mangino
M J
MJ
Kamei
T
T
Flye
M W
MW
D000818:Animals; D002478:Cells, Cultured; D015232:Dinoprostone / Q000096:biosynthesis / Q000502:physiology*; D004731:Endotoxins / Q000494:pharmacology*; D005260:Female; D007213:Indomethacin / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis*; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D011112:Polymyxin B / Q000494:pharmacology; D051381:Rats; D011920:Rats, Inbred WF
D004731:Endotoxins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011112:Polymyxin B; D015232:Dinoprostone; D007213:Indomethacin