The roles of IL-1, IL-6, and TNF alpha in the feeding responses to endotoxin and influenza virus infection in mice

Influenza infection or administration of bacterial endotoxin (lipopolysacch aride, LPS) results in diminished feeding and loss of body weight. It has b een suggested that these effects may be mediated by cytokines, such as inte rleukin-1 (IL-1), interleukin-6 (IL-6), and/or tumor necrosis factor-alpha (TNF alpha). To assess the potential role of these cytokines, we tested the ability of the naturally occurring IL-1-receptor antagonist (IL-1ra), a mo noclonal antibody to mouse IL-6 (IL-6mAb), and a TNF binding protein fragme nt (TNFbp) to antagonize hypophagia induced by intraperitoneally (ip) injec ted mouse IL-1 beta or LPS or by inoculation with influenza virus. Feeding was assessed by measuring the daily intake of food pellets and sweetened mi lk in a 30-min period. The hypophagia induced by mIL-1 beta or LPS was not affected by pretreatment with IL-6mAb. The effects of IL-1 beta were blocke d by IL-1ra but unaffected by TNFbp. TNFbp and IL-1ra given separately both exhibited a tendency to attenuate LPS-induced hypophagia. The effectivenes s of TNFbp plus IL-1ra treatment was similar to that of the individual anta gonists. However, combined treatment with TNFbp, IL-1ra, and IL-6mAb almost completely prevented the depressing effect of LPS on milk intake. The anta gonists were also tested in influenza virus-inoculated mice. IL-1ra was del ivered chronically by osmotic minipumps and was supplemented by treatment w ith TNFbp and IL-6mAb. The treatments slightly attenuated the effects of th e virus on milk intake 48 h after the inoculation and delayed the decrease in body weight. However, over the entire course of the experiment, the trea tment produced very small, statistically nonsignificant, attenuations of th e depressions in milk and food pellet intake. Similar results were obtained with TNFbp alone or the combination of IL-6mAb and TNFbp. The results sugg est that IL-1 beta, TNF alpha, and IL-6 contribute to the hypophagia induce d by LPS. However, antagonism of all three cytokines was not sufficient to prevent the decreases in feeding and loss of body weight induced by influen za virus infection. (C) 1999 Academic Press.