Better explicating the strengths and shortcomings of these models will help refine projections and improve transparency in the years ahead.
Image credit: Witsawat.S.
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Edited by Philippa Marrack, National Jewish Medical and Research Center, Denver, CO (received for review March 4, 2005)
Abstract
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 (gp130 Y757F/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 (gp130 ΔSTAT/ΔSTAT). T cell migration was related to STAT3 activity, because monoallelic deletion of Stat3 in gp130 Y757F/Y757F mice (gp130 Y757F/Y757F:Stat3 +/-) corrected the exaggerated responses observed in gp130 Y757F/Y757F mice. Consequently, STAT3 plays a defining role in IL-6-mediated T cell migration.
Footnotes
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↵ ¶ To whom correspondence should be addressed. E-mail: jonessa{at}cf.ac.uk.
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Author contributions: R.M.M., B.J.J., N.T., and S.A.J. designed research; R.M.M., B.J.J., D.G., A.S.W., C.A.F., and C.R.P. performed research; B.J.J. and M.E. contributed new reagents/analytic tools; R.M.M., B.J.J., N.T., and S.J. analyzed data; and S.A.J. wrote the paper.
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This paper was submitted directly (Track II) to the PNAS office.
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Abbreviations: SES, Staphylococcus epidermidis; sIL-6R, soluble form of the cognate IL-6 receptor.
- Copyright © 2005, The National Academy of Sciences
IL-6 trans-signaling via STAT3 directs T cell infiltration in acute inflammation
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