Abstract
Although peripherally released interleukin (IL)-10 has a critical regulatory role in limiting fever in mild-to-moderate forms of inflammation, its role in regulating the more complex thermoregulatory manifestations of hypothermia and fever noted during severe inflammation is less clear. Using cytokine antagonism, we therefore investigated the involvement of peripherally released IL-10 in mediating hypothermia, fever and inflammation induced by intraperitoneal (IP) administration of a large dose of lipopolysaccharide (LPS). Male Wistar rats (200–250 g) were anaesthetized and implanted intra-abdominally with temperature-sensitive radiotelemeters. Rats were randomly assigned to receive IL-10 antiserum (IL-10AS) or normal sheep serum IP, 4 h before receiving an IP injection of LPS (10 mg/kg) or phosphate-buffered saline (PBS). Inflammatory responses were measured in plasma and tissue samples (spleen, liver and brain) at 90 min and 6 h after the IP injection of LPS or PBS. Administration of LPS induced an initial period of hypothermia (~90 min) after which fever developed. Pre-treating rats with IL-10AS abolished the LPS-induced increase in plasma IL-10 levels, attenuated the hypothermia and increased the amplitude of the fever. Moreover, IL-10AS pre-treatment augmented the LPS-induced increase in plasma levels of tumor necrosis factor-alpha (90 min and 6 h), IL-1β (90 min), prostaglandin E2 (90 min) and IL-6 (6 h), in the periphery, but not the hypothalamus, over the duration of hypothermia and fever. Via its action on the synthesis of inflammatory mediators in the spleen and liver, endogenous IL-10 plays a crucial regulatory role in mediating hypothermia and fever during severe aspectic (LPS-induced) systemic inflammation.
Similar content being viewed by others
References
Aarden LA, De Groot ER, Schaap OL, Lansdorp PM (1987) Production of hybridoma growth factor by human monocytes. Eur J Immunol 17(10):1411–1416
Alexander WS (2002) Suppressors of cytokine signalling (SOCS) in the immune system. Nat Rev Immunol 2(6):410–416
Amuzie CJ, Shinozuka J, Pestka JJ (2009) Induction of suppressors of cytokine signaling by the trichothecene deoxynivalenol in the mouse. Toxicol Sci 111(2):277–287
Baldwin AS Jr (1996) The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol 14:649–683
Barnett RE, Keskey RC, Rao JM, Billeter AT, Kanaan Z, Cheadle WG (2013) Poor outcome in bacterial peritonitis is associated with dysregulated microRNAs and an increased inflammatory response. Surgery 154(3):521–527
Berg DJ, Zhang J, Lauricella DM, Moore SA (2001) IL-10 is a central regulator of cyclooxygenase-2 expression and prostaglandin production. J Immunol 166(4):2674–2680
Berlato C, Cassatella MA, Kinjyo I, Gatto L, Yoshimura A, Bazzoni F (2002) Involvement of suppressor of cytokine signaling-3 as a mediator of the inhibitory effects of IL-10 on lipopolysaccharide-induced macrophage activation. J Immunol 168(12):6404–6411
Bhattacharyya S, Sen P, Wallet M, Long B, Baldwin AS Jr, Tisch R (2004) Immunoregulation of dendritic cells by IL-10 is mediated through suppression of the PI3K/Akt pathway and of IkappaB kinase activity. Blood 104(4):1100–1109
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
Cartmell T, Ball C, Bristow AF, Mitchell D, Poole S (2003) Endogenous interleukin-10 is required for the defervescence of fever evoked by local lipopolysaccharide-induced and Staphylococcus aureus-induced inflammation in rats. J Physiol 549(2):653–664
Cassatella MA, Gasperini S, Bovolenta C, Calzetti F, Vollebregt M, Scapini P, Marchi M, Suzuki R, Suzuki A, Yoshimura A (1999) Interleukin-10 (IL-10) selectively enhances CIS3/SOCS3 mRNA expression in human neutrophils: evidence for an IL-10-induced pathway that is independent of STAT protein activation. Blood 94(8):2880–2889
Damm J, Luheshi GN, Gerstberger R, Roth J, Rummel C (2011) Spatiotemporal nuclear factor interleukin-6 expression in the rat brain during lipopolysaccharide-induced fever is linked to sustained hypothalamic inflammatory target gene induction. J Comp Neurol 519(3):480–505
Denys A, Udalova IA, Smith C, Williams LM, Ciesielski CJ, Campbell J, Andrews C, Kwaitkowski D, Foxwell BM (2002) Evidence for a dual mechanism for IL-10 suppression of TNF-alpha production that does not involve inhibition of p38 mitogen-activated protein kinase or NF-kappa B in primary human macrophages. J Immunol 168(10):4837–4845
Diaz-Munoz MD, Osma-Garcia IC, Cacheiro-Llaguno C, Fresno M, Iniguez MA (2010) Coordinated up-regulation of cyclooxygenase-2 and microsomal prostaglandin E synthase 1 transcription by nuclear factor kappa B and early growth response-1 in macrophages. Cell Signal 22(10):1427–1436
Donnelly RP, Dickensheets H, Finbloom DS (1999) The interleukin-10 signal transduction pathway and regulation of gene expression in mononuclear phagocytes. J Interferon Cytokine Res 19(6):563–573
Dubois RN, Abramson SB, Crofford L, Gupta RA, Simon LS, Van De Putte LB, Lipsky PE (1998) Cyclooxygenase in biology and disease. FASEB J 12(12):1063–1073
Engblom D, Saha S, Engström L, Westman M, Audoly LP, Jakobsson P-J, Blomqvist A (2003) Microsomal prostaglandin E synthase-1 is the central switch during immune-induced pyresis. Nat Neurosci 6(11):1137–1138
Engström L, Ruud J, Eskilsson A, Larsson A, Mackerlova L, Kugelberg U, Qian H, Vasilache AM, Larsson P, Engblom D, Sigvardsson M, Jönsson J-I, Blomqvist A (2012) Lipopolysaccharide-induced fever depends on prostaglandin E2 production specifically in brain endothelial cells. Endocrinology 153(10):4849–4861. doi:10.1210/en.2012-1375
Espevik T, Nissen-Meyer J (1986) A highly sensitive cell line, WEHI 164 clone 13, for measuring cytotoxic factor/tumor necrosis factor from human monocytes. J Immunol Methods 95(1):99–105
Font-Nieves M, Sans-Fons MG, Gorina R, Bonfill-Teixidor E, Salas-Perdomo A, Marquez-Kisinousky L, Santalucia T, Planas AM (2012) Induction of COX-2 enzyme and down-regulation of COX-1 expression by lipopolysaccharide (LPS) control prostaglandin E2 production in astrocytes. J Biol Chem 287(9):6454–6468
Hanada T, Yoshimura A (2002) Regulation of cytokine signaling and inflammation. Cytokine Growth F R 13(4–5):413–421
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(6):838–849
Harden LM, Du Plessis I, Roth J, Loram LC, Poole S, Laburn HP (2011) Differences in the relative involvement of peripherally released interleukin (IL)-6, brain IL-1β and prostanoids in mediating lipopolysaccharide-induced fever and sickness behavior. Psychoneuroendocrinol 36(5):608–622
Holt I, Cooper RG, Hopkins SJ (1991) Relationships between local inflammation, interleukin-6 concentration and the acute phase protein response in arthritis patients. Eur J Clin Invest 21(5):479–484
Ito S, Ansari P, Sakatsume M, Dickensheets H, Vazquez N, Donnelly RP, Larner AC, Finbloom DS (1999) Interleukin-10 inhibits expression of both interferon alpha- and interferon gamma-induced genes by suppressing tyrosine phosphorylation of STAT1. Blood 93(5):1456–1463
Ivanov AI, Romanovsky AA (2004) Prostaglandin E2 as a mediator of fever: synthesis and catabolism. Front Biosci 1(9):1977–1993
Iyer SS, Cheng G (2012) Role of interleukin 10 transcriptional regulation in inflammation and autoimmune disease. Crit Rev Immunol 32(1):23–63
Kluger MJ, Kozak W, Leon LR, Soszynski D, Conn CA (1998) Fever and antipyresis. Prog Brain Res 115:465–475
Kozak W, Conn CA, Klir JJ, Wong GH, Kluger MJ (1995) TNF soluble receptor and antiserum against TNF enhance lipopolysaccharide fever in mice. Am J Physiol Regul Integr Comp Physiol 269(1):R23–R29
Kozak W, Kluger MJ, Tesfaigzi J, Kozak A, Mayfield KP, Wachulec M, Dokladny K (2000) Molecular mechanisms of fever and endogenous antipyresis. Ann N Y Acad Sci 917:121–134
Ledeboer A, Binnekade R, Brevé JJP, Bol JGJM, Tilders FJH, Van Dam A-M (2002) Site-specific modulation of LPS-induced fever and interleukin-1 beta expression in rats by interleukin-10. Am J Physiol Regul Integr Comp Physiol 282(6):R1762–R1772
Leon LR (2002) Invited review: cytokine regulation of fever: studies using gene knockout mice. J Appl Physiol 92(6):2648–2655
Leon LR, Kozak W, Peschon J, Kluger MJ (1997) Exacerbated febrile responses to LPS, but not turpentine, in TNF double receptor-knockout mice. Am J Physiol Regul Integr Comp Physiol 272(2):R563–R569
Leon LR, Kozak W, Rudolph K, Kluger MJ (1999) An antipyretic role for interleukin-10 in LPS fever in mice. Am J Physiol Regul Integr Comp Physiol 276(1):R81–R89
Leon LR, White AA, Kluger MJ (1998) Role of IL-6 and TNF in thermoregulation and survival during sepsis in mice. Am J Physiol Regul Integr Comp Physiol 275(1):R269–R277
Li S, Wang Y, Matsumura K, Ballou LR, Morham SG, Blatteis CM (1999) The febrile response to lipopolysaccharide is blocked in cyclooxygenase-2(−/−), but not in cyclooxygenase-1(−/−) mice. Brain Res 825(1–2):86–94
Liu SF, Newton R, Evans TW, Barnes PJ (1996) Differential regulation of cyclo-oxygenase-1 and cyclo-oxygenase-2 gene expression by lipopolysaccharide treatment in vivo in the rat. Clin Sci (Lond) 90(4):301–306
Liu YW, Tseng HP, Chen LC, Chen BK, Chang WC (2003) Functional cooperation of simian virus 40 promoter factor 1 and CCAAT/enhancer-binding protein beta and delta in lipopolysaccharide-induced gene activation of IL-10 in mouse macrophages. J Immunol 171(2):821–828
Mancini JA, Blood K, Guay J, Gordon R, Claveau D, Chan CC, Riendeau D (2001) Cloning, expression, and up-regulation of inducible rat prostaglandin e synthase during lipopolysaccharide-induced pyresis and adjuvant-induced arthritis. J Biol Chem 276(6):4469–4475
Matsusaka T, Fujikawa K, Nishio Y, Mukaida N, Matsushima K, Kishimoto T, Akira S (1993) Transcription factors NF-IL6 and NF-kappa B synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8. Proc Natl Acad Sci U S A 90(21):10193–10197
Murakami M, Nakatani Y, Tanioka T, Kudo I (2002) Prostaglandin E synthase. Prostaglandins Other Lipid Mediat 68–69:383–399
Murray PJ (2005) The primary mechanism of the IL-10-regulated antiinflammatory response is to selectively inhibit transcription. Proc Natl Acad Sci U S A 102(24):8686–8691
Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates. Academic, San Diego
Rees GS, Ball C, Ward HL, Gee CK, Tarrant G, Mistry Y, Poole S, Bristow AF (1999) Rat interleukin 6: expression in recombinant Escherichia coli, purification and development of a novel ELISA. Cytokine 11(2):95–103
Richwine AF, Sparkman NL, Dilger RN, Buchanan JB, Johnson RW (2009) Cognitive deficits in interleukin-10-deficient mice after peripheral injection of lipopolysaccharide. Brain Behav Immun 23(6):794–802
Rummel C, Sachot C, Poole S, Luheshi GN (2006) Circulating interleukin-6 induces fever through a STAT3-linked activation of COX-2 in the brain. Am J Physiol Regul Integr Comp Physiol 291(5):R1316–R1326
Rummel C, Voss T, Matsumura K, Korte S, Gerstberger R, Roth J, Hübschle T (2005) Nuclear STAT3 translocation in guinea pig and rat brain endothelium during systemic challenge with lipopolysaccharide and interleukin-6. J Comp Neurol 491(1):1–14
Sabat R (2010) IL-10 family of cytokines. Cytokine Growth F R 21(5):315–324
Saccani S, Pantano S, Natoli G (2001) Two waves of nuclear factor kappa B recruitment to target promoters. J Exp Med 193(12):1351–1359
Schneider CP, Schwacha MG, Chaudry IH (2004) The role of interleukin-10 in the regulation of the systemic inflammatory response following trauma-hemorrhage. Biochim Biophys Acta 1689(1):22–32
Schottelius AJ, Mayo MW, Sartor RB, Baldwin AS Jr (1999) Interleukin-10 signaling blocks inhibitor of kappaB kinase activity and nuclear factor kappaB DNA binding. J Biol Chem 274(1):31868–31874
Smith WL, Garavito RM, DeWitt DL (1996) Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and −2. J Biol Chem 271(52):33157–33160
Steiner AA, Hunter JC, Phipps SM, Nucci TB, Oliveira DL, Roberts JL, Scheck AC, Simmons DL, Romanovsky AA (2009) Cyclooxygenase-1 or −2—which one mediates lipopolysaccharide-induced hypothermia? Am J Physiol Regul Integr Comp Physiol 297(2):R485–R494
Stichtenoth DO, Thoren S, Bian H, Peters-Golden M, Jakobsson PJ, Crofford LJ (2001) Microsomal prostaglandin E synthase is regulated by proinflammatory cytokines and glucocorticoids in primary rheumatoid synovial cells. J Immunol 167(1):469–474
Tatro JB (2000) Endogenous antipyretics. Clin Infect Dis 5(31):S190–S201
Wang P, Wu P, Siegel MI, Egan RW, Billah MM (1994) IL-10 inhibits transcription of cytokine genes in human peripheral blood mononuclear cells. J Immunol 153(2):811–816
Yao L, Kan EM, Lu J, Hao A, Dheen ST, Kaur C, Ling EA (2013) Toll-like receptor 4 mediates microglial activation and production of inflammatory mediators in neonatal rat brain following hypoxia: role of TLR4 in hypoxic microglia. J Neuroinflammation 10:23
Acknowledgments
We are grateful to Jolanta Murgott, Doreen Marks, Daniela Ott and Margaret Badenhorst for their expert technical assistance and to the NIBSC for providing the IL-10 antiserum. Funding for this study was provided by the Alexander von Humboldt Foundation of Germany, The Carnegie Corporation of New York and the National Research Foundation of South Africa.
Ethical standard
The experiments comply with the current laws of Germany in which they were performed.
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
ESM 1
(DOCX 768 kb)
Rights and permissions
About this article
Cite this article
Harden, L.M., Rummel, C., Laburn, H.P. et al. Critical role for peripherally-derived interleukin-10 in mediating the thermoregulatory manifestations of fever and hypothermia in severe forms of lipopolysaccharide-induced inflammation. Pflugers Arch - Eur J Physiol 466, 1451–1466 (2014). https://doi.org/10.1007/s00424-013-1371-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00424-013-1371-4