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

Departments of Physiology, Pharmacology and Medicine, Division of Clinical Pharmacology, Medical University of South Carolina, Charleston, South Carolina, USA, Institute of Pharmacology, School of Medicine, University of Messina. Messina, Italy

M. Makhlouf

Departments of Physiology, Pharmacology and Medicine, Division of Clinical Pharmacology, Medical University of South Carolina, Charleston, South Carolina, USA, Institute of Pharmacology, School of Medicine, University of Messina. Messina, Italy

P.V. Halushka

Departments of Physiology, Pharmacology and Medicine, Division of Clinical Pharmacology, Medical University of South Carolina, Charleston, South Carolina, USA, Institute of Pharmacology, School of Medicine, University of Messina. Messina, Italy

A.P. Caputi

Departments of Physiology, Pharmacology and Medicine, Division of Clinical Pharmacology, Medical University of South Carolina, Charleston, South Carolina, USA, Institute of Pharmacology, School of Medicine, University of Messina. Messina, Italy

J.A. Cook

Departments of Physiology, Pharmacology and Medicine, Division of Clinical Pharmacology, Medical University of South Carolina, Charleston, South Carolina, USA, Institute of Pharmacology, School of Medicine, University of Messina. Messina, Italy

Pretreatment of rats with a sublethal dose of human recombinant tumor necrosis factor- (hrTNF, 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), hrTNF 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 F₁ (6-keto-PGF₁) levels, nitric oxide (NO) production, as assessed by nitrite, and interleukin 6 (IL-6) production. In macrophages from hrTNF-pretreated or LPS pretreated rats, basal and LPS-stimulated 6-keto-PGF₁ 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 hrTNF-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 hrTNF-pretreated rats exhibited a marked reduction of the membrane content of the Gi₃ subunit compared to control macrophages, whereas the Gi_1,2 and G_β subunits were not significantly affected. The decrease in Gi₃ in hrTNF treated rats is similar to that previously observed in macrophages from LPS tolerant rats. The results demonstrate that hrTNF 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.

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