Interplay between IFN-gamma and IL-6 signaling governs neutrophil trafficking and apoptosis during acute inflammation.
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.
McLoughlin
Rachel M
RM
Institute of Nephrology, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, United Kingdom.
Witowski
Janusz
J
Robson
Rachel L
RL
Wilkinson
Thomas S
TS
Hurst
Suzanne M
SM
Williams
Anwen S
AS
Williams
John D
JD
Rose-John
Stefan
S
Jones
Simon A
SA
Topley
Nicholas
N
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
D017304:Annexin A5; D007375:Interleukin-1; D015850:Interleukin-6; D011419:Propidium; D007371:Interferon-gamma; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases