A biologic basis for limited Kupffer cell reactivity to portal-derived endotoxin.
Despite continuous exposure to gut-derived endotoxin (lipopolysaccharide) under normal conditions, Kupffer cells (KC) fail to generate detrimental cytokine responses. KC function within a unique microenvironment in which high hepatic arginase activities (25 times greater than those activities in the kidney) result in negligible local L-arginine levels. To evaluate the relevance of this profound arginine deficiency on the physiologic function of KC, the kinetics of tumor necrosis factor (TNF-alpha) production and autoregulatory eicosanoid prostaglandin E2 (PGE2) production were compared in lipopolysaccharide-stimulated KC cultured with (1200 mumol/L) and without (10 mumol/L) L-arginine media. In (+)arginine culture the KC TNF-alpha production peaked early before decreasing as PGE2 production increased. In (-)arginine culture, however, KC TNF-alpha production was significantly (p less than 0.01) reduced, whereas PGE2 production was amplified (p less than 0.01). When cyclooxygenase blockade with indomethacin completely prevented KC production of PGE2 in (-)arginine culture, TNF-alpha production was upregulated (p less than 0.001 vs (-)arginine; p not significant vs (+)arginine). These arginine-specific depression of TNF-alpha responses appeared unique to KC because both TNF-alpha and PGE2 levels increased when peritoneal, pleural, and alveolar macrophages were stimulated by lipopolysaccharide in (-)arginine medium. This PGE2-dependent autoregulation of potentially harmful lipopolysaccharide-induced TNF-alpha responses may reflect an evolutionary adaptation by KC to their local hepatic environment and strategic anatomic position in the portal circuit, which optimally removes endotoxin and naturally protects the host.
Callery
M P
MP
Department of Surgery, Washington University School of Medicine, St. Louis, Mo 63110.
Mangino
M J
MJ
Flye
M W
MW
D000818:Animals; D001120:Arginine / Q000502:physiology*; D002478:Cells, Cultured; D003470:Culture Media; D015232:Dinoprostone / Q000096:biosynthesis*; D005260:Female; D007728:Kupffer Cells / Q000502:physiology*; D008070:Lipopolysaccharides / Q000502:physiology*; D011169:Portal Vein; D011863:Radioimmunoassay; D051381:Rats; D011920:Rats, Inbred WF; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D003470:Culture Media; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D001120:Arginine; D015232:Dinoprostone