IL-6 trans-signaling via STAT3 directs T cell infiltration in acute inflammation.
Interleukin (IL)-6 signaling through its soluble receptor (IL-6 transsignaling) directs transition between innate and acquired immune responses by orchestrating the chemokine-directed attraction and apoptotic clearance of leukocytes. Through analysis of mononuclear cell infiltration in WT and IL-6-deficient mice during peritoneal inflammation, we now report that IL-6 selectively governs T cell infiltration by regulating chemokine secretion (CXCL10, CCL4, CCL5, CCL11, and CCL17) and chemokine receptor (CCR3, CCR4, CCR5, and CXCR3) expression on the CD3+ infiltrate. Although blockade of IL-6 trans-signaling prevented chemokine release, chemokine receptor expression remained unaltered suggesting that this response is regulated by IL-6 itself. To dissect the signaling events promoting T cell migration, inflammation was established in knock-in mice expressing mutated forms of the universal signal-transducing element for IL-6-related cytokines gp130. In mice (gp130Y757F/Y757F) deficient in SHP2 and SOCS3 binding, but presenting hyperactivation of STAT1/3, T cell recruitment and CCL5 expression was enhanced. Conversely, both of these parameters were suppressed in mice with ablated gp130-mediated STAT1/3 activation (gp130DeltaSTAT/DeltaSTAT). T cell migration was related to STAT3 activity, because monoallelic deletion of Stat3 in gp130(Y757F/Y757F) mice (gp130Y757F/Y757F:Stat3+/-) corrected the exaggerated responses observed in gp130Y757F/Y757F mice. Consequently, STAT3 plays a defining role in IL-6-mediated T cell migration.
Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff CF14 4XN, Wales, United Kingdom.
Rachel M
RM
McLoughlin
Brendan J
BJ
Jenkins
Dianne
D
Grail
Anwen S
AS
Williams
Ceri A
CA
Fielding
Clare R
CR
Parker
Matthias
M
Ernst
Nicholas
N
Topley
Simon A
SA
Jones
D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D015153:Blotting, Western; D002465:Cell Movement / Q000276:immunology*; D018925:Chemokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D007249:Inflammation / Q000276:immunology* / Q000382:microbiology; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010537:Peritoneum / Q000382:microbiology; D019707:Receptors, Chemokine / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000276:immunology*; D013212:Staphylococcus epidermidis / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D015534:Trans-Activators / Q000378:metabolism*
D000907:Antibodies, Bacterial; D018925:Chemokines; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D019707:Receptors, Chemokine; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators