IL-6 trans-signaling via STAT3 directs T cell infiltration in acute inflammation

Rachel McLoughlin

Brendan Jenkins

Dianne Grail

Anwen Williams

^{Departments of Medical Biochemistry and Immunology,}^{Nephrology, and}^{Rheumatology, School of Medicine, Cardiff University, Cardiff CF14 4XN, Wales, United Kingdom; and}^{Ludwig Institute for Cancer Research, Colon Molecular and Cell Biology Laboratory, Parkville, Victoria 3050, Australia}

^{To whom correspondence should be addressed. E-mail:}ku.ca.fc@assenoj.

Edited by Philippa Marrack, National Jewish Medical and Research Center, Denver, CO

Received 2005 Mar 4; Accepted 2005 May 23.

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^{) 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^{). T cell migration was related to STAT3 activity, because monoallelic deletion of}Stat3 in gp130^{mice (}gp130^:Stat3^{) corrected the exaggerated responses observed in}gp130^{mice. Consequently, STAT3 plays a defining role in IL-6-mediated T cell migration.}

Keywords: chemokines, cytokines, gp130

Abstract

Interleukin (IL)-6 is traditionally considered a regulator of acute-phase responses and a lymphocyte stimulatory factor (1). However recent advances have highlighted a pivotal role for this cytokine in directing leukocyte trafficking and facilitating transition between innate and acquired immune responses (2, 3). Identification of these IL-6 activities has largely been achieved through an increased understanding of the regulatory properties of its soluble receptor, whereas better appreciation of IL-6 signaling has led researchers to consider the interplay between IL-6 and other cytokines (4–7). These studies collectively underline a role for IL-6 in governing inflammation and have emphasized the therapeutic potential of targeting IL-6 as a strategy for the management of infectious and inflammatory diseases (8, 9).

IL-6 responses are transmitted through gp130, which serves as the universal signal-transducing receptor subunit for all IL-6-related cytokines (10, 11). Although this classically occurs through IL-6 binding to its membrane-bound receptor (IL-6R), it is clear that a soluble form of the cognate IL-6 receptor (sIL-6R) affords IL-6 with an alternative mechanism of gp130 activation. This additional mode of cell activation is termed IL-6 trans-signaling and results from formation of a sIL-6R/IL-6 complex, which can directly bind cellular gp130 (2). Because gp130 is ubiquitously expressed within tissue, trans-signaling provides IL-6 with the capacity to activate cells that would not intrinsically respond to IL-6 itself (2).

Studies have documented inherent roles for IL-6 trans-signaling in a number of biological processes, including its involvement in leukocyte trafficking and activation (2, 3). Although initial observations in IL-6-deficient (IL-6^{) mice noted that IL-6 suppressed neutrophil accumulation at sites of infection or inflammation (}12, 13), it is evident that neutrophil clearance and their subsequent replacement by a more sustained population of mononuclear leukocytes is governed by the sIL-6R (5, 14). In particular, IL-6 trans-signaling defines the nature of the inflammatory infiltrate by controlling leukocyte apoptosis and the expression of inflammatory chemokines and adhesion molecules (5, 13–18). This event is a critical step in the successful resolution of any inflammatory response and defines an immunological switch from innate to acquired immunity at sites of inflammation.

In terms of mononuclear leukocytes, IL-6-mediated signaling is associated with the activation of a number of cellular events important in host defense and chronic disease progression. With respect to monocytes/macrophages, IL-6 affects cellular differentiation (19–21). However, the role of IL-6 in lymphocyte activation may have more profound consequences, where it controls T cell polarization (22–24), IL-2-dependent cell proliferation (25, 26), L-selectin (CD62L) adhesion (18), B cell activation, and antibody production (25). Furthermore, the ability of IL-6 to rescue T cells from entering apoptosis (17, 27–30) may have a considerable bearing in the progression of chronic inflammation. Indeed, sIL-6R-mediated trans-signaling promotes T cell expression of antiapoptotic regulators (17, 30), whereas blockade of sIL-6R signaling in experimental models suppresses the pathogenesis of Crohn's disease and rheumatoid arthritis (17, 31). Through in vivo analysis of experimental peritoneal inflammation, studies presented herein now show that IL-6 activation of STAT3 promotes T cell recruitment.

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Acknowledgments

This work was supported through The Wellcome Trust and Arthritis Research Campaign project grants.

Acknowledgments

Notes

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.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: SES, Staphylococcus epidermidis; sIL-6R, soluble form of the cognate IL-6 receptor.

Notes

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: SES, Staphylococcus epidermidis; sIL-6R, soluble form of the cognate IL-6 receptor.

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