Abstract
The purpose of the present study was to better understand the events involved in the febrile response induced by cecal ligation and puncture (CLP), a complex infectious process. To this end, we conducted in vivo experiments in rats examining (1) fever development, (2) bacterial number in the infection focus and in blood, (3) peripheral and hypothalamic synthesis of cytokines, (4) hypothalamic and cerebrospinal fluid (CSF) synthesis of prostaglandin E2 (PGE2), (5) the effect of anti-IL-6 antibody on fever, and (6) the effect of celecoxib on fever and hypothalamic synthesis of PGE2 after CLP induction. We found that CLP promotes fever and animal death depending on the number of punctures. The peak of CLP-induced fever overlapped with the maximal increase in the number of bacteria in the infectious focus and blood, which occurred at 6 and 12 h. The peak of the febrile response also coincided with increased amounts of interleukin (IL)-1β, IL-6 and IL-10 in the peritoneal exudate and serum; IL-6 in the hypothalamus and PGE2 in the CSF and predominantly in the hypothalamus. Moreover, intracerebroventricularly injected anti-IL-6 antibody reduced the febrile response while celecoxib reduced the fever and PGE2 amount in the hypothalamus induced by CLP. Tumor necrosis factor (TNF)-α peaked at 3 h at all sites studied. Conversely, IL-10 concentration decreased in the hypothalamus. These findings show that the peak of CLP-induced fever is accompanied by an increase of bacteria in peritoneal fluid (local infection) and blood; local synthesis of pyrogenic (IL-1β, IL-6) and antipyretic (IL-10) cytokines and central production of IL-6 and PGE2, suggesting that these last are the central mediators of this response.
Similar content being viewed by others
References
Roth J, De Souza GE (2001) Fever induction pathways: evidence from responses to systemic or local cytokine formation. Braz J Med Biol Res 34(3):301–314
Pessini AC, Santos DR, Arantes EC, Souza GE (2006) Mediators involved in the febrile response induced by Tityus serrulatus scorpion venom in rats. Toxicon 48(5):556–566
Kanashiro A, Pessini AC, Machado RR, Malvar Ddo C, Aguiar FA, Soares DM, do Vale ML, de Souza GE (2009) Characterization and pharmacological evaluation of febrile response on zymosan-induced arthritis in rats. Am J Physiol Regul Integr Comp Physiol 296(5):R1631–R1640
Blatteis CM, Li S, Li Z, Feleder C, Perlik V (2005) Cytokines, PGE2 and endotoxic fever: a re-assessment. Prostaglandins Other Lipid Mediat 76(1–4):1–18 (Review)
Blatteis CM (2006) Endotoxic fever: new concepts of its regulation suggest new approaches to its management. Pharmacol Ther 111(1):194–223 (Review)
Roth J, Rummel C, Barth SW, Gerstberger R, Hübschle T (2006) Molecular aspects of fever and hyperthermia. Neurol Clin 24(3):421–439 (Review)
Roth J, Rummel C, Barth SW, Gerstberger R, Hübschle T (2009) Molecular aspects of fever and hyperthermia. Immunol Allergy Clin North Am 29(2):229–245
Machado RR, Soares DM, Proudfoot AE, Souza GE (2007) CCR1 and CCR5 chemokine receptors are involved in fever induced by LPS (E. coli) and RANTES in rats. Brain Res 1161:21–31
Soares DM, Machado RR, Yamashiro LH, Melo MC, Souza GE (2008) Cytokine-induced neutrophil chemoattractant (CINC)-1 induces fever by a prostaglandin-dependent mechanism in rats. Brain Res 1233:79–88
Roth J (2006) Endogenous antipyretics. Clin Chim Acta 371(1–2):13–24 (Review)
Gourine AV, Rudolph K, Tesfaigzi J, Kluger MJ (1998) Role of hypothalamic interleukin-1beta in fever induced by cecal ligation and puncture in rats. Am J Physiol 275(3 Pt 2):R754–R761
Johnson JD, O’Connor KA, Deak T, Stark M, Watkins LR, Maier SF (2002) Prior stressor exposure sensitizes LPS-induced cytokine production. Brain Behav Immun 16:461–476
Johnson JD, O’Connor KA, Hansen MK, Watkins LR, Maier SF (2003) Effects of prior stress on LPS-induced cytokine and sickness responses. Am J Physiol Regul Integr Comp Physiol 284:R422–R432
Wichterman KA, Baue AE, Chaudry IH (1980) Sepsis and septic shock–a review of laboratory models and a proposal. J Surg Res 29(2):189–201
Baker CC, Chaudry IH, Gaines HO, Baue AE (1983) Evaluation of factors affecting mortality rate after sepsis in a murine cecal ligation and puncture model. Surgery 94(2):331–335
Hubbard WJ, Choudhry M, Schwacha MG, Kerby JD, Rue LW III, Bland KI, Chaudry IH (2005) Cecal ligation and puncture. Shock 24:52–57
Leon LR, White AA, Kluger MJ (1998) Role of IL-6 and TNF in thermoregulation and survival during sepsis in mice. Am J Physiol 275:R269–R277
Ebong S, Call D, Nemzek J, Bolgos G, Newcomb D, Remick D (1999) Immunopathologic alterations in murine models of sepsis of increasing severity. Infect Immun 67:6603–6610
Torres-Dueñas D, Benjamim CF, Ferreira SH, Cunha FQ (2006) Failure of neutrophil migration to infectious focus and cardiovascular changes on sepsis in rats: effects of the inhibition of nitric oxide production, removal of infectious focus, and antimicrobial treatment. Shock 25:267–276
Gordon CJ (1990) Thermal biology of the laboratory rat. Physiol Behav 47:963–991
Romanovsky AA, Ivanov AI, Shimansky YP (2002) Selected contribution: ambient temperature for experiments in rats: a new method for determining the zone of thermal neutrality. J Appl Physiol 92:2667–2679
Fabricio AS, Veiga FH, Cristofoletti R, Navarra P, Souza GE (2005) The effects of selective and nonselective cyclooxygenase inhibitors on endothelin-1-induced fever in rats. Am J Physiol Regul Integr Comp Physiol 288:R671–R677
Consiglio AR, Lucion AB (2000) Technique for collecting cerebrospinal fluid in the cisterna magna of non-anesthetized rats. Brain Res Protoc 5:109–114
Fabricio AS, Tringali G, Pozzoli G, Melo MC, Vercesi JA, Souza GE, Navarra P (2006) Interleukin-1 mediates endothelin-1-induced fever and prostaglandin production in the preoptic area of rats. Am J Physiol Regul Integr Comp Physiol 290:R1515–R1523
Bone RC, Fisher CJ, Clemmer TD, Slotman GJ, Metz CA, Balk RA (1989) Sepsis syndrome: a valid clinical entity. Crit Care Med 17:389–393
Briese E (1986) Circadian body temperature rhythm and behavior of rats in thermoclines. Physiol Behav 37:839–847
Refinetti R, Menaker M (1992) The circadian rhythm of body temperature. Physiol Behav 51:613–637
Gordon CJ (1993) Twenty-four hour rhythms of selected ambient temperature in rat and hamster. Physiol Behav 53:257–263
Nolan A, Kobayashi H, Naveed B, Kelly A, Hoshino Y, Hoshino S, Karulf MR, Rom WN, Weiden MD, Gold JA (2009) Differential role for CD80 and CD86 in the regulation of the innate immune response in murine polymicrobial sepsis. PLoS One 12:e6600
Cavaillon JM, Adib-Conquy M, Fitting C, Adrie C, Payen D (2003) Cytokine cascade in sepsis. Scand J Infect Dis 35:535–544 (Review)
Campisi J, Hansen MK, O’Connor KA, Biedenkapp JC, Watkins LR, Maier SF, Fleshner M (2003) Circulating cytokines and endotoxin are not necessary for the activation of the sickness or corticosterone response produced by peripheral E. coli challenge. J Appl Physiol 95(5):1873–1882
Werner MF, Fraga D, Melo MC, Souza GE, Zampronio AR (2003) Importance of the vagus nerve for fever and neutrophil migration induced by intraperitoneal LPS injection. Inflamm Res 52(7):291–296
Zampronio AR, Hoadley ME, Luheshi G, Rothwell NJ, de Souza GE, Hopkins SJ (2000) Interleukin (IL)-6 release and fever induced by a pre-formed pyrogenic factor (PFPF) derived from LPS-stimulated macrophages. Eur Cytokine Netw 11(4):589–596
Soares DM, Figueiredo MJ, Martins JM, Machado RR, Sorgi C, Faciolli LH, Alves-Filho JC, Cunha FQ, Souza GE (2011) A crucial role for IL-6 in the CNS of rats during fever induced by the injection of live E. coli. Med Microbiol Immunol (Epub ahead of print)
Muenzer JT, Davis CG, Dunne BS, Unsinger J, Dunne WM, Hotchkiss RS (2006) Pneumonia after cecal ligation and puncture: a clinically relevant “two-hit” model of sepsis. Shock 26(6):565–570
Damas P, Ledoux D, Nys M, Vrindts Y, De Groote D, Franchimont P, Lamy M (1992) Cytokine serum level during severe sepsis in human IL-6 as a marker of severity. Ann Surg 215:356–362
Casey LC, Balk RA, Bone RC (1993) Plasma cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome. Ann Intern Med 119:771–778
Fisher CJ Jr, Opal SM, Dhainaut JF, Stephens S, Zimmerman JL, Nightingale P, Harris SJ, Schein RM, Panacek EA, Vincent JL et al (1993) Influence of an anti-tumor necrosis factor monoclonal antibody on cytokine levels in patients with sepsis. Crit Care Med 21:318–327
Baigrie RJ, Lamont PM, Kwiatkowski D, Dallman MJ, Morris PJ (1992) Systemic cytokine response after major surgery. Br J Surg 79:757–760
Turnbull IR, Javadi P, Buchman TG, Hotchkiss RS, Karl IE, Coopersmith CM (2004) Antibiotics improve survival in sepsis independent of injury severity but do not change mortality in mice with markedly elevated interleukin 6 levels. Shock 21:121–125
Vianna RC, Gomes RN, Bozza FA, Amâncio RT, Bozza PT, David CM, Castro-Faria-Neto HC (2004) Antibiotic treatment in a murine model of sepsis: impact on cytokines and endotoxin release. Shock 21:115–120
Remick DG, Bolgos GR, Siddiqui J, Shin J, Nemzek JA (2002) Six at six: interleukin-6 measured 6 h after the initiation of sepsis predicts mortality over 3 days. Shock 17:463–467
Frink M, van Griensven M, Kobbe P, Brin T, Zeckey C, Vaske B, Krettek C, Hildebrand F (2009) IL-6 predicts organ dysfunction and mortality in patients with multiple injuries. Scand J Trauma Resusc Emerg Med 27:17–49
Riedemann NC, Neff TA, Guo RF, Bernacki KD, Laudes IJ, Sarma JV, Lambris JD, Ward PA (2003) Protective effects of IL-6 blockade in sepsis are linked to reduced C5a receptor expression. J Immunol 170(1):503–507
Chai Z, Gatti S, Toniatti C, Poli V, Bartfai T (1996) Interleukin (IL)-6 gene expression in the central nervous system is necessary for fever response to lipopolysaccharide or IL-1 beta: a study on IL-6-deficient mice. J Exp Med 183:311–316
Helle M, Brakenhoff JP, De Groot ER, Aarden LA (1988) Interleukin 6 is involved in interleukin 1-induced activities. Eur J Immunol 18:957–959
Chida D, Iwakura Y (2007) Peripheral TNFalpha, but not peripheral IL-1, requires endogenous IL-1 or TNFalpha induction in the brain for the febrile response. Biochem Biophys Res Commun 364:765–770
Puma C, Danik M, Quirion R, Ramon F, Williams S (2001) The chemokine interleukin-8 acutely reduces Ca+2 currents in identified cholinergic septal neurons expressing CXCR1and CXCR2 receptor mRNAs. J Neurochem 78:960–971
Campbell SJ, Wilcockson DC, Butchart AG, Perry VH, Anthony DC (2002) Altered chemokine expression in the spinal cord and brain contributes to differential interleukin-1beta-induced neutrophil recruitment. J Neurochem 83:432–441
Muenzer JT, Davis CG, Chang K, Schmidt RE, Dunne WM, Coopersmith CM, Hotchkiss RS (2010) Characterization and modulation of the immunosuppressive phase of sepsis. Infect Immun 78(4):1582–1592
Wiersinga WJ (2011) Current insights in sepsis: from pathogenesis to new treatment targets. Curr Opin Crit Care 17(5):480–486
Ledeboer A, Brevé JJP, Poole S, Tilders FJH, Van Dam AM (2000) Interleukin-10, interleukin-4 and transforming growth factor-β differentially regulate lipopolysaccharide-induced production of proinflammatory cytokines and nitric oxide in co-cultures of rat astroglial and microglial cells. Glia 30:134–142
De Waal Malefyt R, Abrams J, Bennett B, Figdor C, De Vries JE (1991) Interleukin-10 (IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med 174:1209–1220
Mitchell JA, Belvisi MG, Akarasereenont P, Robbins RA, Kwon OJ, Croxtall J, Barnes PJ, Vane JR (1994) Induction of cyclo-oxygenase-2 by cytokines in human pulmonary epithelial cells: regulation by dexamethasone. Br J Pharmacol 113:1008–1014
Singer CA, Baker KJ, McCaffrey A, AuCoin DP, Dechert MA, Gerthoffer WT (2003) p38 MAPK and NF-kappaB mediate COX-2 expression in human airway myocytes. Am J Physiol Lung Cell Mol Physiol 285:L1087–L1098
Malvar Ddo C, Soares DM, Fabrício AS, Kanashiro A, Machado RR, Figueiredo MJ, Rae GA, de Souza GE (2011) The antipyretic effect of dipyrone is unrelated to inhibition of PGE(2) synthesis in the hypothalamus. Br J Pharmacol 162(6):1401–1409
Cao C, Matsumura K, Shirakawa N, Maeda M, Jikihara I, Kobayashi S, Watanabe Y (2001) Pyrogenic cytokines injected into the rat cerebral ventricle induce cyclooxygenase-2 in brain endothelial cells and also up regulate their receptors. Eur J Neurosci 13:1781–1790
Oka Y, Ibuki T, Matsumura K, Namba M, Yamazaki Y, Poole S, Tanaka Y, Kobayashi S (2007) Interleukin-6 is a candidate molecule that transmits inflammatory information to the CNS. Neuroscience 145:530–538
Nakamura Y, Nakamura K, Matsumura K, Kobayashi S, Kaneko T, Morrison SF (2005) Direct pyrogenic input from prostaglandin EP3 receptor-expressing preoptic neurons to the dorsomedial hypothalamus. Eur J Neurosci 22:3137–3146
Lazarus M, Yoshida K, Coppari R, Bass CE, Mochizuki T, Lowell BB et al (2007) EP3 prostaglandin receptors in the median preoptic nucleus are critical for fever responses. Nat Neurosci 10:1131–1133
Harden LM, du Plessis I, Poole S, Laburn HP (2008) Interleukin (IL)-6 and IL-1 beta act synergistically within the brain to induce sickness behavior and fever in rats. Brain Behav Immun 22:838–849
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Figueiredo, M.J., de Melo Soares, D., Martins, J.M. et al. Febrile response induced by cecal ligation and puncture (CLP) in rats: involvement of prostaglandin E2 and cytokines. Med Microbiol Immunol 201, 219–229 (2012). https://doi.org/10.1007/s00430-011-0225-y
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00430-011-0225-y