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Interruption of macrophage-derived IL-27(p28) production by IL-10 during sepsis requires STAT3 but not SOCS3.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2014 Dec 01; Vol. 193 (11), pp. 5668-77. Date of Electronic Publication: 2014 Oct 27. - Publication Year :
- 2014
-
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.<br /> (Copyright © 2014 by The American Association of Immunologists, Inc.)
- Subjects :
- Adaptor Proteins, Vesicular Transport genetics
Adaptor Proteins, Vesicular Transport metabolism
Animals
Antibodies, Blocking administration & dosage
Bacterial Load
Cecum surgery
Cells, Cultured
Disease Models, Animal
Humans
Interleukin-10 genetics
Interleukins immunology
Macrophages drug effects
Macrophages microbiology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Myeloid Differentiation Factor 88 genetics
Myeloid Differentiation Factor 88 metabolism
Oxidative Stress drug effects
Oxidative Stress genetics
Receptors, Cytokine genetics
Receptors, Interleukin
STAT3 Transcription Factor genetics
Suppressor of Cytokine Signaling 3 Protein
Suppressor of Cytokine Signaling Proteins genetics
Suppressor of Cytokine Signaling Proteins metabolism
Toll-Like Receptor 4 immunology
Interleukin-10 metabolism
Interleukins metabolism
Macrophages physiology
STAT3 Transcription Factor metabolism
Sepsis immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 193
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 25348624
- Full Text :
- https://doi.org/10.4049/jimmunol.1302280