title: Interplay between IFN-gamma and IL-6 signaling governs neutrophil trafficking and apoptosis during acute inflammation.
abstract: Regulated recruitment and clearance of neutrophils (PMN) is the hallmark of competent host defense and resolution of inflammation. We now report that IFN-gamma controls PMN infiltration and modulates IL-6 signaling through its soluble receptor (sIL-6R) to promote their apoptosis and clearance. Induction of peritoneal inflammation in IFN-gamma-deficient (IFN-gamma-/-) mice emphasized that the initial rate of PMN recruitment was impaired. This defect in PMN recruitment was also associated with the suppressed intraperitoneal expression of IL-1beta and IL-6. Reconstitution of IFN-gamma signaling restored the rate of PMN infiltration and IL-6 levels and was accompanied by normalization of PMN-activating CXC chemokine expression. To test whether local IL-6 signaling modulated PMN recruitment, inflammation was induced in IFN-gamma-/- and IL-6-/- mice and cytokine signaling adapted by intraperitoneal sIL-6R-IL-6 fusion protein (HYPER-IL-6) or IFN-gamma. Although HYPER-IL-6 attenuated PMN influx in IFN-gamma-/- mice, IFN-gamma had no effect on PMN infiltration in IL-6-/- mice. Examination of the leukocyte infiltrate from IFN-gamma-/-, IL-6-/-, and wild-type mice showed that apoptosis was aberrant in the absence of IFN-gamma and IL-6 as a result of impaired sIL-6R signaling. These data emphasize a pivotal role for IFN-gamma in regulating innate immunity through control of both the recruitment and clearance phases of PMN trafficking.
authors.affiliation: Institute of Nephrology, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, United Kingdom.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: McLoughlin
authors.forename: Janusz
authors.initials: J
authors.lastname: Witowski
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Robson
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Wilkinson
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Hurst
authors.forename: Anwen S
authors.initials: AS
authors.lastname: Williams
authors.forename: John D
authors.initials: JD
authors.lastname: Williams
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.forename: Simon A
authors.initials: SA
authors.lastname: Jones
authors.forename: Nicholas
authors.initials: N
authors.lastname: Topley
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology*; D010537:Peritoneum / Q000166:cytology / Q000276:immunology; D011419:Propidium / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D017304:Annexin A5; D007375:Interleukin-1; D015850:Interleukin-6; D011419:Propidium; D007371:Interferon-gamma; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases