Increased prostacyclin and PGE2 stimulated cAMP production by macrophages from endotoxin-tolerant rats

• Published in: American Journal of Physiology: Cell Physiology Vol. 274; no. 5; p. C1238
• Main Authors: Makhlouf, Michel A, Fernando, Lawrence P, Gettys, Thomas W, Halushka, Perry V, Cook, James A
• Format: Journal Article
• Language: English
• Published: United States 01.05.1998
• Subjects: Adenylyl Cyclases - metabolism; Animals; Blotting, Northern; Cell Membrane - metabolism; Cyclic AMP - biosynthesis; Dinoprostone - analogs & derivatives; Dinoprostone - metabolism; Dinoprostone - pharmacology; Drug Tolerance - physiology; Endotoxins - pharmacology; Epoprostenol - analogs & derivatives; Epoprostenol - pharmacology; Isoproterenol - pharmacology; Lipopolysaccharides - pharmacology; Macrophages - drug effects; Macrophages - metabolism; Macrophages - physiology; Male; Rats; Rats, Inbred Strains; Receptors, Epoprostenol; Receptors, Prostaglandin - genetics; Receptors, Prostaglandin E - genetics; Receptors, Prostaglandin E, EP4 Subtype; RNA, Messenger - metabolism
• ISSN: 0363-6143; 0002-9513; 1522-1563
• DOI: 10.1152/ajpcell.1998.274.5.c1238

Departments of 1  Physiology, 2  Medicine, and 3  Pharmacology, Medical University of South Carolina, Charleston, South Carolina 29425 Sublethal administration of lipopolysaccharide (LPS) renders rats tolerant to multiple lethal stimuli. Tolerant macrophages exhibit differential alterations in LPS-stimulated cytokine and inflammatory mediator release. Increased cAMP levels stimulated by PGE 2 or prostacyclin (PGI 2 ) result in differential effects on LPS-induced cytokine release and protect against the pathophysiological changes of endotoxemia. In the present studies, we sought to determine whether PGE 2 - and PGI 2 -stimulated cAMP levels are altered in tolerant macrophages. Incubation of macrophages with cicaprost or 11-deoxy-PGE 1 in the presence of phosphodiesterase inhibitors resulted in significantly higher (2.5- to 6.5-fold) cAMP concentrations in tolerant macrophages compared with control. In contrast, isoproterenol-stimulated cAMP levels were not significantly different between control and tolerant cells. Also, incubation of tolerant macrophages with LPS did not result in significantly elevated cAMP levels. Prostacyclin (IP) receptor mRNA levels were significantly increased in tolerant cells compared with controls, whereas [ 3 H]PGE 2 binding and PGE 2 EP4 receptor mRNA levels were not significantly changed. These studies suggest that LPS tolerance induces selective alterations in eicosanoid regulation of cAMP formation. G proteins; pertussis toxin; forskolin; cicaprost; lipopolysaccharide; prostaglandin E 2