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

Cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) are assumed to mediate anorexia during bacterial infectio ns. To improve our understanding of the role that these two cytokines serve in mediating infection during anorexia, we investigated the ability of pen toxifylline (PTX), a potent inhibitor of TNF-alpha production, to block the anorectic effects of the bacterial products lipopolysaccharide (LPS) and m uramyl dipeptide (MDP) in rats. Intraperitoneally injected PTX (100 mg/kg b ody wt) completely eliminated the anorectic effect of intraperitoneally inj ected LPS (100 mg/kg body wt) and attenuated the anorectic effect of a high er dose of intraperitoneally injected LPS (250 mug/kg body wt). Concurrentl y, PTX pretreatment suppressed low-dose LPS-induced TNF-alpha production by more than 95% and IL-1 beta production 39%, as measured by ELISA. Similarl y, high-dose LPS-induced TNF-alpha production was reduced by similar to 90% . PTX administration also attenuated the tolerance that is normally observe d with a second injection of LPS. In addition, PTX pretreatment attenuated the hypophagic effect of intraperitoneally injected MDP (2 mg/kg body wt) b ut had no effect on the anorectic response to intraperitoneally injected re combinant human TNF-alpha (150 ug/kg body wt). The results suggest that sup pression of TNF-alpha production is sufficient to attenuate LPS- and MDP-in duced anorexia. This is consistent with the hypothesis that TNF-alpha plays a major role in the anorexia associated with bacterial infection.