title: A crucial role for IL-6 in the CNS of rats during fever induced by the injection of live E. coli.
abstract: Interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6 have been established as important mediators of fever induced by lipopolysaccharide (LPS) from Gram-negative bacteria. Whether these pro-inflammatory cytokines are also important in mediating fever induced by live bacteria remains less certain. We therefore investigated the following: (1) the synthesis of TNF-α, IL-1β, and IL-6 during E. coli-induced fever and (2) the effect of blocking the action of cytokines within the brain on E. coli-induced fever. Body or tail skin temperature (bT or Tsk, respectively) was measured by biotelemetry or telethermometry, every 30 min, during 6 or 24 h. Depending on the number of colony-forming units (CFU) injected i.p., administration of E. coli induced a long-lasting increase in bT of male Wistar rats. The duration of fever did not correlate with the number of CFU found in peritoneal cavity or blood. Because 2.5 × 10(8) CFU induced a sustained fever without inducing a state of sepsis/severe infection, this dose was used in subsequent experiments. The E. coli-induced increase in bT was preceded by a decrease in Tsk, reflecting a thermoregulatory response. TNF-α, IL-1β, and IL-6 were detected at 3 h in serum of animals injected i.p. with E. coli. In the peritoneal exudates, TNF-α, IL-1β, and IL-6 were detected at 0.5 and 3 h after E. coli administration. Moreover, both IL-1β and IL-6, but not TNF-α, were found in the cerebrospinal fluid (CSF) and hypothalamus of animals injected with E. coli. Although pre-treatment (i.c.v., 2 μl, 15 min before) with anti-IL-6 antibody (anti-IL-6, 5 μg) reduced E. coli-induced fever, pre-treatment with either IL-1 receptor antagonist (IL-1ra, 200 μg) or soluble TNF receptor I (sTNFRI, 500 ng) had no effect on the fever response. In conclusion, replicating E. coli promotes an integrated thermoregulatory response in which the central action of IL-6, but not IL-1 and TNF, appears to be important.
authors.affiliation: Laboratory of Pharmacology, Department of Physic and Chemistry, University of São Paulo, Ribeirão Preto, São Paulo, Brazil. denisms@usp.br
authors.forename: Denis M
authors.initials: DM
authors.lastname: Soares
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Figueiredo
authors.forename: Juliano Manvailer
authors.initials: JM
authors.lastname: Martins
authors.forename: Renes Resende
authors.initials: RR
authors.lastname: Machado
authors.forename: Carlos
authors.initials: C
authors.lastname: Sorgi
authors.forename: Lucia Helena
authors.initials: LH
authors.lastname: Faciolli
authors.forename: José C
authors.initials: JC
authors.lastname: Alves-Filho
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.forename: Glória E P
authors.initials: GE
authors.lastname: Souza
mesh_terms: D000818:Animals; D001831:Body Temperature; D002555:Cerebrospinal Fluid / Q000276:immunology*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004926:Escherichia coli / Q000276:immunology / Q000472:pathogenicity*; D004927:Escherichia coli Infections / Q000276:immunology* / Q000382:microbiology / Q000401:mortality / Q000503:physiopathology*; D005334:Fever / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D007031:Hypothalamus / Q000276:immunology; D007375:Interleukin-1 / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D007375:Interleukin-1; D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha