title: Protection from lethal septic peritonitis by neutralizing the biological function of interleukin 27.
abstract: The immune response to bacterial infections must be tightly controlled to guarantee pathogen elimination while preventing tissue damage by uncontrolled inflammation. Here, we demonstrate a key role of interleukin (IL)-27 in regulating this critical balance. IL-27 was rapidly induced during murine experimental peritonitis induced by cecal ligation and puncture (CLP). Furthermore, mice deficient for the EBI3 subunit of IL-27 were resistant to CLP-induced septic peritonitis as compared with wild-type controls, and this effect could be suppressed by injection of recombinant single-chain IL-27. EBI3-/- mice displayed significantly enhanced neutrophil migration and oxidative burst capacity during CLP, resulting in enhanced bacterial clearance and local control of infection. Subsequent studies demonstrated that IL-27 directly suppresses endotoxin-induced production of reactive oxygen intermediates by isolated primary granulocytes and macrophages. Finally, in vivo blockade of IL-27 function using a newly designed soluble IL-27 receptor fusion protein led to significantly increased survival after CLP as compared with control-treated mice. Collectively, these data identify IL-27 as a key negative regulator of innate immune cell function in septic peritonitis. Furthermore, in vivo blockade of IL-27 is a novel potential therapeutic target for treatment of sepsis.
authors.affiliation: Laboratory of Immunology, I. Medical Clinic, University of Mainz, 55131 Mainz, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wirtz
authors.forename: Ingrid
authors.initials: I
authors.lastname: Tubbe
authors.forename: Peter R
authors.initials: PR
authors.lastname: Galle
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Schild
authors.forename: Mark
authors.initials: M
authors.lastname: Birkenbach
authors.forename: Richard S
authors.initials: RS
authors.lastname: Blumberg
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
mesh_terms: D000818:Animals; D001419:Bacteria; D015536:Down-Regulation / Q000235:genetics; D006098:Granulocytes / Q000276:immunology; D007113:Immunity, Innate / Q000276:immunology; D007378:Interleukins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010538:Peritonitis / Q000276:immunology* / Q000517:prevention & control*; D021122:Protein Subunits / Q000172:deficiency / Q000276:immunology; D018123:Receptors, Interleukin / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D018805:Sepsis / Q000276:immunology* / Q000517:prevention & control*; D012995:Solubility; D015854:Up-Regulation / Q000235:genetics
chemical_list: C486767:Il27 protein, mouse; D007378:Interleukins; D021122:Protein Subunits; D018123:Receptors, Interleukin; D011993:Recombinant Fusion Proteins