Interplay between IFN-γ and IL-6 signaling governs neutrophil trafficking and apoptosis during acute inflammation
Rachel M. McLoughlin, … , Simon A. Jones, Nicholas Topley
Rachel M. McLoughlin, … , Simon A. Jones, Nicholas Topley
Published August 15, 2003
Citation Information: J Clin Invest. 2003;112(4):598-607. https://doi.org/10.1172/JCI17129.
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Article Immunology

Interplay between IFN-γ 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-γ 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-γ–deficient (IFN-γ–/–) 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-1β and IL-6. Reconstitution of IFN-γ 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-γ–/– and IL-6–/– mice and cytokine signaling adapted by intraperitoneal sIL-6R–IL-6 fusion protein (HYPER-IL-6) or IFN-γ. Although HYPER-IL-6 attenuated PMN influx in IFN-γ–/– mice, IFN-γ had no effect on PMN infiltration in IL-6–/– mice. Examination of the leukocyte infiltrate from IFN-γ–/–, IL-6–/–, and wild-type mice showed that apoptosis was aberrant in the absence of IFN-γ and IL-6 as a result of impaired sIL-6R signaling. These data emphasize a pivotal role for IFN-γ in regulating innate immunity through control of both the recruitment and clearance phases of PMN trafficking.

Authors

Rachel M. McLoughlin, Janusz Witowski, Rachel L. Robson, Thomas S. Wilkinson, Suzanne M. Hurst, Anwen S. Williams, John D. Williams, Stefan Rose-John, Simon A. Jones, Nicholas Topley

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Regulation of IL-6 production by IL-1β and IFN-γ in vitro and in vivo. G...
Regulation of IL-6 production by IL-1β and IFN-γ in vitro and in vivo. Growth-arrested HPMC were (a) incubated with medium alone or IL-1β (100 pg/ml) in the presence or absence of IFN-γ (100 U/ml). At specific time points, IL-6 levels were quantified using ELISA (*P < 0.05, a significant increase versus the additive value of IL-1β plus IFN-γ alone). (b) Northern blot analysis of total RNA isolated from HPMC incubated for 3 hours with medium and IL-1β (100 pg/ml) in the presence or absence of IFN-γ (100 U/ml). Representative results for three separate experiments are shown. (c) HPMC were stimulated with medium alone (lane 1), HYPER-IL-6 (500 pg/ml, lane 2), IFN-γ (100 U/ml, lane 3), IL-1β (100 pg/ml, lane 4), or a combination of IL-1β and IFN-γ (lane 5). At the indicated intervals, nuclear extracts were prepared and NF-κB activation was monitored by EMSA. (d) Composition of the NF-κB complex was determined by supershift using antibodies against p50 (lane 2) and p65 (lane 3). No antibodies were included in lane 1. Results are representative of three separate experiments performed with HPMC from different donors. (e) Wild-type mice were intraperitoneally administered with PBS, IL-1β (100 ng per mouse), IFN-γ (0.5 U per mouse), or a combination of IL-1β and IFN-γ at these doses. After 1 hour, mice were sacrificed and IL-6 was quantified (*P < 0.05 versus PBS alone; **P < 0.05, a significant increase versus the additive value of IL-1β plus IFN-γ alone).