ALTERED MACROPHAGE FUNCTION IN TUMOR-NECROSIS-FACTOR-ALPHA-INDUCED AND ENDOTOXIN-INDUCED TOLERANCE

Pretreatment of rats with a sublethal dose of human recombinant tumor necrosis factor-a (hrTNF alpha, 10 mu g/kg i.p.) or Salmonella enterit idis LPS (100 mu g/kg, i.p.) prevented death when a lethal dose of S. enteritidis lipopolysaccharide (LPS, 15 mg/kg i.p.) was administered 2 4 h later, The resistance to the lethal effect of LPS was associated w ith similar alterations of the functional phenotype of peritoneal macr ophages from both groups, In ex vivo studies, peritoneal macrophages w ere harvested 24 h after vehicle (control), hrTNF alpha or LPS injecti on and stimulated in vitro with LPS, In macrophages collected from con trol rats, LPS stimulated arachidonic acid (AA) metabolism, as assesse d by 6-keto-prostaglandin F-1 alpha (6-keto-PGF(1 alpha)) levels, nitr ic oxide (NO) production, as assessed by nitrite, and interleukin 6 (I L-6) production, In macrophages from hrTNF alpha-pretreated or LPS pre treated rats, basal and LPS-stimulated 6-keto-PGF(1 alpha) production were significantly reduced compared to controls, while nitrite product ion was increased (P < 0.001), LPS induced IL-6 synthesis was not affe cted in macrophages from hrTNF(alpha)-pretreated rats but was signific antly reduced in stimulated macrophages from LPS treated rats, Further more, the macrophage membrane content of guanine nucleotide binding re gulatory (G) protein subunits was determined, Macrophages collected fr om hrTNF(alpha)-pretreated rats exhibited a marked reduction of the me mbrane content of the Gi(alpha 3) subunit compared to control macropha ges, whereas the Gi(alpha 1,2) and G(beta) subunits were not significa ntly affected, The decrease in Gi(alpha 3) in hrTNF alpha treated rats is similar to that previously observed in macrophages from LPS tolera nt rats, The results demonstrate that hrTNF alpha induces cross tolera nce to the lethal effect of LPS, and that tolerance induced by TNF or LPS is associated with differential changes in peritoneal macrophage m ediator production, These changes may, in part, be a consequence of al tered signal transduction via specific G proteins,