Altered macrophage function in tumor necrosis factor α- and endotoxin-induced tolerance

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Abstract
Pretreatment of rats with a sublethal dose of human recombinant tumor necrosis factor-α (hrTNFα, 10 μg/kg i.p.) or Salmonella enteritidis LPS (100 μg/kg, i.p.) prevented death when a lethal dose of S. enteritidis lipopolysaccharide (LPS, 15 mg/kg i.p.) was administered 24 h later. The resistance to the lethal effect of LPS was associated with similar alterations of the functional phenotype of peritoneal macrophages from both groups. In ex vivo studies, peritoneal macrophages were harvested 24 h after vehicle (control), hrTNFα or LPS injection and stimulated in vitro with LPS. In macrophages collected from control rats, LPS stimulated arachidonic acid (AA) metabolism, as assessed by 6-keto-prostaglandin F1α (6-keto-PGF1α) levels, nitric oxide (NO) production, as assessed by nitrite, and interleukin 6 (IL-6) production. In macrophages from hrTNFα-pretreated or LPS pretreated rats, basal and LPS-stimulated 6-keto-PGF1α production were significantly reduced compared to controls, while nitrite production was increased (P < 0.001). LPS induced IL-6 synthesis was not affected in macrophages from hrTNFα-pretreated rats but was significantly reduced in stimulated macrophages from LPS treated rats. Furthermore, the macrophage membrane content of guanine nucleotide binding regulatory (G) protein subunits was determined. Macrophages collected from hrTNFα-pretreated rats exhibited a marked reduction of the membrane content of the Giα3 subunit compared to control macrophages, whereas the Giα1,2 and Gβ subunits were not significantly affected. The decrease in Giα3 in hrTNFα treated rats is similar to that previously observed in macrophages from LPS tolerant rats. The results demonstrate that hrTNFα induces cross tolerance to the lethal effect of LPS, and that tolerance induced by TNF or LPS is associated with differential changes in peritoneal macrophage mediator production. These changes may, in part, be a consequence of altered signal transduction via specific G proteins.