title: Interruption of macrophage-derived IL-27(p28) production by IL-10 during sepsis requires STAT3 but not SOCS3.
abstract: Severe sepsis and septic shock are leading causes of morbidity and mortality worldwide. Infection-associated inflammation promotes the development and progression of adverse outcomes in sepsis. The effects of heterodimeric IL-27 (p28/EBI3) have been implicated in the natural course of sepsis, whereas the molecular mechanisms underlying the regulation of gene expression and release of IL-27 in sepsis are poorly understood. We studied the events regulating the p28 subunit of IL-27 in endotoxic shock and polymicrobial sepsis following cecal ligation and puncture. Neutralizing Abs to IL-27(p28) improved survival rates, restricted cytokine release, and reduced bacterial burden in C57BL/6 mice during sepsis. Genetic disruption of IL-27 signaling enhanced the respiratory burst of macrophages. Experiments using splenectomized mice or treatment with clodronate liposomes suggested that macrophages in the spleen may be a significant source of IL-27(p28) during sepsis. In cultures of TLR4-activated macrophages, the frequency of F4/80(+)CD11b(+)IL-27(p28)(+) cells was reduced by the addition of IL-10. IL-10 antagonized both MyD88-dependent and TRIF-dependent release of IL-27(p28). Genetic deletion of STAT3 in Tie2-Cre/STAT3flox macrophages completely interrupted the inhibition of IL-27(p28) by IL-10 after TLR4 activation. In contrast, IL-10 remained fully active to suppress IL-27(p28) with deletion of SOCS3 in Tie2-Cre/SOCS3flox macrophages. Blockade of IL-10R by Ab or genetic deficiency of IL-10 resulted in 3-5-fold higher concentrations of IL-27(p28) in endotoxic shock and polymicrobial sepsis. Our studies identify IL-10 as a critical suppressing factor for IL-27(p28) production during infection-associated inflammation. These findings may be helpful for a beneficial manipulation of adverse IL-27(p28) release during sepsis.
authors.affiliation: Center for Thrombosis and Hemostasis, University Medical Center Mainz, 55131 Mainz, Germany; Department of Hematology, Oncology, and Pneumology, University Medical Center Mainz, 55131 Mainz, Germany; markus.bosmann@unimedizin-mainz.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Bosmann
authors.affiliation: Center for Thrombosis and Hemostasis, University Medical Center Mainz, 55131 Mainz, Germany;
authors.forename: Norman F
authors.initials: NF
authors.lastname: Russkamp
authors.affiliation: Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, A-1210 Vienna, Austria;
authors.forename: Birgit
authors.initials: B
authors.lastname: Strobl
authors.affiliation: Center for Thrombosis and Hemostasis, University Medical Center Mainz, 55131 Mainz, Germany;
authors.forename: Julian
authors.initials: J
authors.lastname: Roewe
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors.forename: Liza
authors.initials: L
authors.lastname: Balouzian
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109;
authors.forename: Florence
authors.initials: F
authors.lastname: Pache
authors.affiliation: Institute for Immunology, University Medical Center Mainz, 55131 Mainz, Germany; and.
authors.forename: Markus P
authors.initials: MP
authors.lastname: Radsak
authors.affiliation: Department of Molecular Cell Biology, Free University Medical Center, 1081 BT Amsterdam, the Netherlands.
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109;
authors.forename: Firas S
authors.initials: FS
authors.lastname: Zetoune
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109;
authors.forename: J Vidya
authors.initials: JV
authors.lastname: Sarma
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109;
authors.forename: Gabriel
authors.initials: G
authors.lastname: Núñez
authors.affiliation: Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, A-1210 Vienna, Austria;
authors.forename: Mathias
authors.initials: M
authors.lastname: Müller
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Murray
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109;
authors.forename: Peter A
authors.initials: PA
authors.lastname: Ward
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D058491:Bacterial Load; D002432:Cecum / Q000601:surgery; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D007378:Interleukins / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D018121:Receptors, Cytokine / Q000235:genetics; D018123:Receptors, Interleukin; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis / Q000276:immunology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D019138:Antibodies, Blocking; D016753:Interleukin-10; D007378:Interleukins; D053594:Myeloid Differentiation Factor 88; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051197:Toll-Like Receptor 4; C486767:Il27 protein, mouse; C484747:Il27ra protein, mouse; C491411:Socs3 protein, mouse; C476286:Ticam1 protein, mouse