title: Anomalous role of tumor necrosis factor alpha in experimental enterococcal infection.
abstract: The murine D-galactosamine (D-gal) model of tumor necrosis factor alpha (TNF-alpha) hypersensitization was used as an initial tool to investigate the potential contribution of TNF-alpha to lethal intraperitoneal (i.p.) infection with Enterococcus faecalis. D-gal sensitized mice to lethal E. faecalis infection, whereas dexamethasone and neutralizing anti-TNF-alpha antibody protected D-gal-treated, E. faecalis-infected mice, implicating TNF-alpha in the lethal response to E. faecalis infection in D-gal-treated mice. Circulating TNF-alpha was undetectable for at least 8 h following i.p. E. faecalis infection, although low peritoneal levels of TNF-alpha were detected within 3 h, suggesting that localized TNF-alpha production contributed to the lethal response to E. faecalis infection in D-gal-treated mice. Although i.p. E. faecalis infection failed to induce a detectable systemic TNF-alpha response, circulating Interleukin-6 (IL-6) was detected within 3 h of infection. IL-6 was also detected in the peritoneum within an hour of infection, prior to the appearance of peritoneal TNF-alpha. In striking contrast to in vivo results, E. faecalis induced a potent and rapid TNF-alpha response from both mouse peritoneal macrophages and the RAW 264.7 cell line in vitro. This led us to hypothesize that TNF-alpha production in response to E. faecalis infection is suppressed by IL-6 in vivo. In vitro experiments demonstrated a statistically significant, but modest, inhibitory effect of IL-6 on TNF-alpha production by RAW cells stimulated with E. faecalis. Collectively, these data indicate that acute, lethal E. faecalis infection appears to induce an unusual cytokine response that differs in character from that previously described for most other gram-positive and gram-negative bacteria.
authors.affiliation: Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, 64108, USA. papasianc@umkc.edu
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Papasian
authors.forename: Richard
authors.initials: R
authors.lastname: Silverstein
authors.forename: Jian Jun
authors.initials: JJ
authors.lastname: Gao
authors.forename: David M
authors.initials: DM
authors.lastname: Bamberger
authors.forename: David C
authors.initials: DC
authors.lastname: Morrison
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D013293:Enterococcus faecalis / Q000276:immunology* / Q000472:pathogenicity*; D005260:Female; D005688:Galactosamine / Q000008:administration & dosage; D016908:Gram-Positive Bacterial Infections / Q000276:immunology / Q000382:microbiology / Q000401:mortality*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000502:physiology*
chemical_list: D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine