Inhibition of TNF-alpha production contributes to the attenuation of LPS-induced hypophagia by pentoxifylline

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2000-12, Vol.279 (6), p.2113-R2120
• Main Authors: Porter, M. H, Hrupka, B. J, Altreuther, G, Arnold, M, Langhans, W
• Format: Article
• Language: English
• Subjects: Acetylmuramyl-Alanyl-Isoglutamine - pharmacology; Animals; Anorexia - chemically induced; Anorexia - physiopathology; Drug Tolerance; Humans; Hyperphagia - chemically induced; Hyperphagia - physiopathology; Interleukin-1 - biosynthesis; Interleukin-1 - blood; Lipopolysaccharides - pharmacology; Male; Pentoxifylline - pharmacology; Rats; Rats, Sprague-Dawley; Recombinant Proteins - pharmacology; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - pharmacology; Virulence Factors, Bordetella - pharmacology
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.2000.279.6.r2113

Institute of Animal Sciences, Swiss Federal Institute of Technology, 8092 Zurich, Switzerland Cytokines such as tumor necrosis factor- (TNF- ) and interleukin-1 (IL-1 ) are assumed to mediate anorexia during bacterial infections. To improve our understanding of the role that these two cytokines serve in mediating infection during anorexia, we investigated the ability of pentoxifylline (PTX), a potent inhibitor of TNF- production, to block the anorectic effects of the bacterial products lipopolysaccharide (LPS) and muramyl dipeptide (MDP) in rats. Intraperitoneally injected PTX (100 mg/kg body wt) completely eliminated the anorectic effect of intraperitoneally injected LPS (100 µg/kg body wt) and attenuated the anorectic effect of a higher dose of intraperitoneally injected LPS (250 µg/kg body wt). Concurrently, PTX pretreatment suppressed low-dose LPS-induced TNF- production by more than 95% and IL-1 production 39%, as measured by ELISA. Similarly, high-dose LPS-induced TNF- production was reduced by ~90%. PTX administration also attenuated the tolerance that is normally observed with a second injection of LPS. In addition, PTX pretreatment attenuated the hypophagic effect of intraperitoneally injected MDP (2 mg/kg body wt) but had no effect on the anorectic response to intraperitoneally injected recombinant human TNF- (150 ug/kg body wt). The results suggest that suppression of TNF- production is sufficient to attenuate LPS- and MDP-induced anorexia. This is consistent with the hypothesis that TNF- plays a major role in the anorexia associated with bacterial infection. lipopolysaccharide; muramyl dipeptide; interleukin-1 ; cytokines; tolerance; food intake