Anti-gamma interferon and anti-interleukin-6 antibodies affect staphylococcal enterotoxin B-induced weight loss, hypoglycemia, and cytokine release in D-galactosamine-sensitized and unsensitized mice

Abstract

Administration of staphylococcal enterotoxin B (SEB) to BALB/c mice was found to induce a cytokine release syndrome hallmarked by weight loss and hypoglycemia. A neutralizing monoclonal antibody against gamma interferon (IFN-␥) given before SEB counteracted weight loss and prevented hypoglycemia. This protective effect of anti-IFN-␥ antibody was associated with decreased IFN-␥ levels in serum; tumor necrosis factor (TNF) and interleukin-6 (IL-6) levels remained unchanged. A monoclonal anti-IL-6 antibody, known for its ability to cause accumulation of biologically active IL-6 in the circulation, did not modify SEB-induced body weight loss or hypoglycemia. Levels of TNF, IFN-␥, and IL-6 in serum were all more elevated in anti-IL-6-treated mice than in corresponding SEB-challenged control mice. In D-galactosamine-sensitized mice, SEB-induced weight loss but not hypoglycemia was more severe, resulting mostly in death within 24 h. Higher levels of biologically active TNF and IFN-␥ in serum were noted in these mice than in mice receiving SEB only. In D-galactosaminesensitized mice, anti-IFN-␥ antibody did prevent hypoglycemia but failed to reduce the severity of the syndrome. Again, TNF levels in anti-IFN-␥-treated mice remained unchanged. Pretreatment with anti-IL-6 antibody temporarily attenuated SEB-induced hypoglycemia in sensitized mice. Thus, at 6 h post-SEB injection, anti-IL-6-treated mice were less hypoglycemic than corresponding controls. However, at 24 h, hypoglycemia was significantly aggravated. Concomitantly, IL-6 levels were dramatically increased. Neither anti-IFN-␥ nor anti-IL-6 antibody treatment modulated mortality levels in D-galactosamine-sensitized mice. The data obtained with anti-IFN-␥ antibody clearly indicate that endogenous IFN-␥ is instrumental in bringing about hypoglycemia and body weight loss in mice exposed to SEB but also that hypoglycemia is not a crucial determinant of mortality in D-galactosamine-sensitized mice. The data obtained with anti-IL-6 antibody indicate that endogenous IL-6 is involved in regulating the levels of TNF and IFN-␥ in serum.

Cancer cachexia prevention via physical exercise: molecular mechanisms

“…Furthermore, elevated IL-6 infusion and exercise has been seen to attenuate endotoxin-induced increases in TNF-α in humans [74]. The fact that TNF-α levels are markedly elevated in anti-IL-6-treated mice [100,101] adds further support that circulating IL-6 is involved in the regulation of TNF-α. Another anti-inflammatory IL-6 function is the stimulation of IL-1ra and IL-10 [86] antiinflammatory cytokines, in addition to the release of soluble TNF-α receptors, sTNF-r1 and sTNF-r2 [77].…”

Possible beneficial role of exercise in modulating low‐grade inflammation in the elderly

“…The suppressive effect occurs at the level of transcription in human peripheral blood mononuclear cells (Schindler et al, 1990). Following endotoxin infusion in vivo, levels of TNF were markedly elevated in anti-IL-6-treated mice (Matthys, Mitera, Heremans, Van Damme, Billiau, 1995) and an IL-6 deficient knock-out mice compared with control mice, suggesting that circulating IL-6 regulates TNF levels (Mizuhara, 1994).…”

Exercise and IL‐6 infusion inhibit endotoxin‐induced TNF‐α production in humans

“…TNF-α and interleukin (IL)-6 are tightly linked, thus TNF-α stimulates IL-6 production. However, in vitro studies (10) as well as animal studies (11,12) suggest that IL-6 may inhibit TNF-α production, and it has been suggested that IL-6 should be classified as an antiinflammatory cytokine (13) Exercise induces increased plasma catecholamine levels (6), and it has recently been demonstrated that epinephrine infusion inhibited endotoxin-induced in vivo TNF-α appearance and also increased IL-10 release (14). Therefore, we hypothesized that exercise would inhibit an endotoxin-stimulated increase in circulating levels of TNF-α.…”