IL-6 Trans-Signaling via STAT3 Directs T Cell Infiltration in Acute Inflammation

• Published in: Proceedings of the National Academy of Sciences - PNAS 2005-07, Vol.102 (27), p.9589-9594
• Main Authors: McLoughlin, Rachel M., Jenkins, Brendan J., Grail, Dianne, Williams, Anwen S., Fielding, Ceri A., Parker, Clare R., Ernst, Matthias, Topley, Nicholas, Jones, Simon A., Marrack, Philippa
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antibodies, Bacterial - immunology; B lymphocytes; Biological Sciences; Blotting, Western; Cell adhesion & migration; Cell Movement - immunology; Chemokine receptors; Chemokines; Chemokines - metabolism; Cytokines; DNA-Binding Proteins - metabolism; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Gene Expression Regulation - immunology; Inflammation; Inflammation - immunology; Inflammation - microbiology; Interleukin-6 - metabolism; Leukocytes; Lymphocytes; Mice; Mice, Knockout; Peritoneum - microbiology; Receptors; Receptors, Chemokine - metabolism; Signal transduction; Signal Transduction - immunology; Staphylococcus epidermidis - immunology; STAT3 Transcription Factor; T cell receptors; T lymphocytes; T-Lymphocytes - immunology; Trans-Activators - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0501794102

Interleukin (IL)-6 signaling through its soluble receptor (IL-6 trans-signaling) 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 (gp130Y757 F/ Y757 F) 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 (gp130Δ STAT/Δ STAT). T cell migration was related to STAT3 activity, because monoallelic deletion of Stat3 in gp130Y757 F/ Y757 Fmice (gp130Y757 F/ Y757 F: Stat3+/-) corrected the exaggerated responses observed in gp130Y757 F/ Y757 Fmice. Consequently, STAT3 plays a defining role in IL-6-mediated T cell migration.