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

Abstract

Cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) 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-alpha 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 microg/kg body wt) and attenuated the anorectic effect of a higher dose of intraperitoneally injected LPS (250 microg/kg body wt). Concurrently, PTX pretreatment suppressed low-dose LPS-induced TNF-alpha production by more than 95% and IL-1beta production 39%, as measured by ELISA. Similarly, high-dose LPS-induced TNF-alpha production was reduced by approximately 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-alpha (150 ug/kg body wt). The results suggest that suppression of TNF-alpha production is sufficient to attenuate LPS- and MDP-induced anorexia. This is consistent with the hypothesis that TNF-alpha plays a major role in the anorexia associated with bacterial infection.

The viral mimic, polyinosinic:polycytidylic acid, induces fever in rats via an interleukin-1-dependent mechanism

“…The observations made in the present study exclude IL-1 and, by extension, IL-6 as mediators for poly I:C-induced anorexia but do not, however, exclude TNF-␣, which increases significantly after poly I:C treatment and is not inhibited by IL-1ra. This cytokine has previously been implicated in mediating a decrease in food intake after infection and inflammation (38,47) and provides a viable alternative to IL-1 and IL-6 for mediating the anorexic effects of poly I:C. However, this would need to be confirmed by neutralization studies in vivo. Other cytokines may also be involved.…”

COX-2 inhibition attenuates anorexia during systemic inflammation without impairing cytokine production

“…Unlike other agents that attenuate inflammation-induced anorexia, such as the phosphodiesterase inhibitor pentoxyphylline, calcium channel blockers, and glucocorticoids that block proximal events in the response to LPS (17,18,30), COX-2-selective drugs decrease anorexia without diminishing the cytokine response. Previous studies have demonstrated that NSAIDs may actually increase, rather than decrease, proximal events in the response during inflammation, such as induction of TNF-␣ (25), and our data extend this analysis by demonstrating no intermediate-to long-term reduction in IL-6 production.…”

“…Similar to bacterial infection, LPS administration results in fever, robust cytokine production, and anorexia in rodents (20,30). Inhibition of cytokine production or action after LPS, specifically tumor necrosis factor (TNF)-␣ and interleukin (IL)-1␤, attenuates LPS-induced anorexia (29,30).…”

“…Similar to bacterial infection, LPS administration results in fever, robust cytokine production, and anorexia in rodents (20,30). Inhibition of cytokine production or action after LPS, specifically tumor necrosis factor (TNF)-␣ and interleukin (IL)-1␤, attenuates LPS-induced anorexia (29,30). However, inhibition of these proximal mediators of the inflammatory cascade would be expected to compromise survival in the setting of a live, replicating pathogen as suggested by the increased susceptibility of mice with genetic deficiency of TNF receptor 1 (31), , and interferon-␥ (6) to infection with bacterial agents such as Listeria monocytogenes.…”

Hyperleptinemia and reduced TNF-α secretion cause resistance of db/db mice to endotoxin

“…A severe inflammatory response can, therefore, cause deleterious changes in nutrition that adversely affect growth, reproduction, and the immune system (3). LPS, a gram-negative bacterial endotoxin, has been extensively used for experimental induction of an inflammatory response; its administration results in anorexia, fever, and increased cytokine production in rodents (27,33). The anorexia and host responses to LPS infection are mediated by IL-1␤ and TNF-␣ (7).…”