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Critical role for peripherally-derived interleukin-10 in mediating the thermoregulatory manifestations of fever and hypothermia in severe forms of lipopolysaccharide-induced inflammation

  • Lois M. HardenEmail author
  • Christoph Rummel
  • Helen P. Laburn
  • Jelena Damm
  • Florian Wiegand
  • Stephen Poole
  • Rüdiger Gerstberger
  • Joachim Roth
Neuroscience

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.

Keywords

Fever Hypothermia Anti-inflammatory cytokines Peritonitis 

Notes

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.

Supplementary material

424_2013_1371_MOESM1_ESM.docx (769 kb)
ESM 1 (DOCX 768 kb)

References

  1. 1.
    Aarden LA, De Groot ER, Schaap OL, Lansdorp PM (1987) Production of hybridoma growth factor by human monocytes. Eur J Immunol 17(10):1411–1416PubMedCrossRefGoogle Scholar
  2. 2.
    Alexander WS (2002) Suppressors of cytokine signalling (SOCS) in the immune system. Nat Rev Immunol 2(6):410–416PubMedGoogle Scholar
  3. 3.
    Amuzie CJ, Shinozuka J, Pestka JJ (2009) Induction of suppressors of cytokine signaling by the trichothecene deoxynivalenol in the mouse. Toxicol Sci 111(2):277–287PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Baldwin AS Jr (1996) The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol 14:649–683PubMedCrossRefGoogle Scholar
  5. 5.
    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):521–527PubMedCrossRefGoogle Scholar
  6. 6.
    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):2674–2680PubMedCrossRefGoogle Scholar
  7. 7.
    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):6404–6411PubMedCrossRefGoogle Scholar
  8. 8.
    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):1100–1109PubMedCrossRefGoogle Scholar
  9. 9.
    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):1–18PubMedCrossRefGoogle Scholar
  10. 10.
    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):653–664PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    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):2880–2889PubMedGoogle Scholar
  12. 12.
    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):480–505PubMedCrossRefGoogle Scholar
  13. 13.
    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):4837–4845PubMedCrossRefGoogle Scholar
  14. 14.
    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):1427–1436PubMedCrossRefGoogle Scholar
  15. 15.
    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):563–573PubMedCrossRefGoogle Scholar
  16. 16.
    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):1063–1073PubMedGoogle Scholar
  17. 17.
    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):1137–1138PubMedCrossRefGoogle Scholar
  18. 18.
    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 PubMedCrossRefGoogle Scholar
  19. 19.
    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):99–105PubMedCrossRefGoogle Scholar
  20. 20.
    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):6454–6468PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Hanada T, Yoshimura A (2002) Regulation of cytokine signaling and inflammation. Cytokine Growth F R 13(4–5):413–421CrossRefGoogle Scholar
  22. 22.
    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):838–849PubMedCrossRefGoogle Scholar
  23. 23.
    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):608–622CrossRefGoogle Scholar
  24. 24.
    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):479–484PubMedCrossRefGoogle Scholar
  25. 25.
    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):1456–1463PubMedGoogle Scholar
  26. 26.
    Ivanov AI, Romanovsky AA (2004) Prostaglandin E2 as a mediator of fever: synthesis and catabolism. Front Biosci 1(9):1977–1993CrossRefGoogle Scholar
  27. 27.
    Iyer SS, Cheng G (2012) Role of interleukin 10 transcriptional regulation in inflammation and autoimmune disease. Crit Rev Immunol 32(1):23–63PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Kluger MJ, Kozak W, Leon LR, Soszynski D, Conn CA (1998) Fever and antipyresis. Prog Brain Res 115:465–475PubMedCrossRefGoogle Scholar
  29. 29.
    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–R29Google Scholar
  30. 30.
    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 917:121–134PubMedCrossRefGoogle Scholar
  31. 31.
    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–R1772PubMedGoogle Scholar
  32. 32.
    Leon LR (2002) Invited review: cytokine regulation of fever: studies using gene knockout mice. J Appl Physiol 92(6):2648–2655PubMedGoogle Scholar
  33. 33.
    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–R569Google Scholar
  34. 34.
    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–R89Google Scholar
  35. 35.
    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–R277Google Scholar
  36. 36.
    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):86–94PubMedCrossRefGoogle Scholar
  37. 37.
    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):301–306Google Scholar
  38. 38.
    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):821–828PubMedCrossRefGoogle Scholar
  39. 39.
    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):4469–4475PubMedCrossRefGoogle Scholar
  40. 40.
    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):10193–10197PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Murakami M, Nakatani Y, Tanioka T, Kudo I (2002) Prostaglandin E synthase. Prostaglandins Other Lipid Mediat 68–69:383–399PubMedCrossRefGoogle Scholar
  42. 42.
    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):8686–8691PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates. Academic, San DiegoGoogle Scholar
  44. 44.
    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):95–103PubMedCrossRefGoogle Scholar
  45. 45.
    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):794–802PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    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–R1326PubMedCrossRefGoogle Scholar
  47. 47.
    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):1–14PubMedCrossRefGoogle Scholar
  48. 48.
    Sabat R (2010) IL-10 family of cytokines. Cytokine Growth F R 21(5):315–324CrossRefGoogle Scholar
  49. 49.
    Saccani S, Pantano S, Natoli G (2001) Two waves of nuclear factor kappa B recruitment to target promoters. J Exp Med 193(12):1351–1359PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    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):22–32PubMedCrossRefGoogle Scholar
  51. 51.
    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):31868–31874PubMedCrossRefGoogle Scholar
  52. 52.
    Smith WL, Garavito RM, DeWitt DL (1996) Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and −2. J Biol Chem 271(52):33157–33160PubMedCrossRefGoogle Scholar
  53. 53.
    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–R494PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    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):469–474PubMedCrossRefGoogle Scholar
  55. 55.
    Tatro JB (2000) Endogenous antipyretics. Clin Infect Dis 5(31):S190–S201CrossRefGoogle Scholar
  56. 56.
    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):811–816PubMedGoogle Scholar
  57. 57.
    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 10:23PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Lois M. Harden
    • 1
    • 2
    Email author
  • Christoph Rummel
    • 2
  • Helen P. Laburn
    • 1
  • Jelena Damm
    • 2
  • Florian Wiegand
    • 2
  • Stephen Poole
    • 3
  • Rüdiger Gerstberger
    • 2
  • Joachim Roth
    • 2
  1. 1.Brain Function Research Group, School of Physiology, Faculty of Health SciencesUniversity of the WitwatersrandJohannesburgSouth Africa
  2. 2.Institut für Veterinär-PhysiologieJustus-Liebig-Universität GiessenGiessenGermany
  3. 3.Biotherapeutics GroupNational Institute for Biological Standards and ControlHertsUK

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