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IL-6 regulates neutrophil trafficking during acute inflammation via STAT3

Fielding, Ceri Alan ORCID:, McLoughlin, Rachel Mary, McLeod, Louise, Colmont, Chantal Sophie, Najdovska, Meri, Grail, Dianne, Ernst, Matthias, Jones, Simon Arnett ORCID:, Topley, Nicholas and Jenkins, Brendan J. 2008. IL-6 regulates neutrophil trafficking during acute inflammation via STAT3. Journal of Immunology 181 (3) , pp. 2189-2195.

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The successful resolution of inflammation is dependent upon the coordinated transition from the initial recruitment of neutrophils to a more sustained population of mononuclear cells. IL-6, which signals via the common receptor subunit gp130, represents a crucial checkpoint regulator of neutrophil trafficking during the inflammatory response by orchestrating chemokine production and leukocyte apoptosis. However, the relative contribution of specific IL-6-dependent signaling pathways to these processes remains unresolved. To define the receptor-mediated signaling events responsible for IL-6-driven neutrophil trafficking, we used a series of gp130 knockin mutant mice displaying altered IL-6-signaling capacities in an experimental model of acute peritoneal inflammation. Hyperactivation of STAT1 and STAT3 in gp130Y757F/Y757F mice led to a more rapid clearance of neutrophils, and this coincided with a pronounced down-modulation in production of the neutrophil-attracting chemokine CXCL1/KC. By contrast, the proportion of apoptotic neutrophils in the inflammatory infiltrate remained unaffected. In gp130Y757F/Y757F mice lacking IL-6, neutrophil trafficking and CXCL1/KC levels were normal, and this corresponded with a reduction in the level of STAT1/3 activity. Furthermore, monoallelic ablation of Stat3 in gp130Y757F/Y757F mice specifically reduced STAT3 activity and corrected both the rapid clearance of neutrophils and impaired CXCL1/KC production. Conversely, genetic deletion of Stat1 in gp130Y757F/Y757F mice failed to rescue the altered responses observed in gp130Y757F/Y757F mice. Collectively, these data genetically define that IL-6-driven signaling via STAT3, but not STAT1, limits the inflammatory recruitment of neutrophils, and therefore represents a critical event for the termination of the innate immune response.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QH Natural history > QH426 Genetics
Q Science > QR Microbiology > QR180 Immunology
R Medicine > RM Therapeutics. Pharmacology
Publisher: American Association of Immunologists
ISSN: 1550-6606
Last Modified: 18 Oct 2022 14:24

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