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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Figure 1

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IFN-γ deficiency modulates the PMN infiltration in SES-induced peritonea...
IFN-γ deficiency modulates the PMN infiltration in SES-induced peritoneal inflammation. (a) Wild-type and IFN-γ–/– mice were intraperitoneally administered with PBS, SES, or SES in combination with IFN-γ (50 U per mouse). At defined time points, PMN infiltration was assessed using differential cell counting (*P < 0.05, a significant increase versus IFN-γ–/– plus SES; #P < 0.05, a significant decrease versus IFN-γ–/– plus SES). (b) KC levels were quantified by ELISA (*P < 0.05, a significant increase versus IFN-γ–/– plus SES). Results are expressed as the mean ± SEM of 10 mice per treatment. (c) The rate of PMN infiltration in response to exogenous administration of IFN-γ (0.5–500 U per mouse) to IFN-γ–/– mice. Filled circles represent IFN-γ–/– mice receiving SES in combination with defined doses of IFN-γ. The open circle illustrates the rate of PMN infiltration in wild-type mice.