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Blood, 15 September 2007, Vol. 110, No. 6, pp. 1748-1755. Prepublished online as a Blood First Edition Paper on June 13, 2007; DOI 10.1182/blood-2007-01-067918. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-01-067918v1 110/6/1748    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chalaris, A. Articles by Scheller, J. Search for Related Content PubMed PubMed Citation Articles by Chalaris, A. Articles by Scheller, J. Related Collections Immunobiology Phagocytes Apoptosis Signal Transduction Chemokines, Cytokines, and Interleukins Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CHEMOKINES, CYTOKINES, AND INTERLEUKINS Apoptosis is a natural stimulus of IL6R shedding and contributes to the proinflammatory trans-signaling function of neutrophils Athena Chalaris1, Björn Rabe1, Krzysztof Paliga1, Hans Lange2, Tamas Laskay3, Ceri A. Fielding4, Simon A. Jones4, Stefan Rose-John1, and Jürgen Scheller1 1 Department of Biochemistry, Christian-Albrechts-University, Kiel, Germany; 2 Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel, Germany; 3 Institute of Medical Microbiology and Hygiene, University Hospital Schleswig-Holstein, Lübeck, Germany; 4 Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff, United Kingdom Interleukin 6 (IL6) trans-signaling has emerged as a prominent regulator of immune responses during both innate and acquired immunity. Regulation of IL6 trans-signaling is reliant upon the release of soluble IL6 receptor (sIL6R), which binds IL6 to create an agonistic IL6/sIL6R complex capable of activating cell types that would not normally respond to IL6 itself. Here we show that intrinsic and extrinsic apoptotic stimulation by DNA damage, cytokine deprivation, and Fas stimulation promotes shedding of sIL6R. Apoptosis-induced shedding of the IL6R was caspase dependent but PKC independent, with inhibition of ADAM17 preventing IL6R shedding. Such insight is relevant to the control of acute inflammation, where transition from the initial neutrophil infiltration to a more sustained population of mononuclear cells is essential for the resolution of the inflammatory process. This transitional event is governed by IL6 trans-signaling. This study demonstrates that IL6R is shed from apoptotic human neutrophils. In vivo studies in a murine inflammation model showed that neutrophil depletion resulted in reduced local sIL6R levels and a concomitant decrease in mononuclear cells, suggesting that apoptosis-induced IL6R shedding from neutrophils promotes IL6 trans-signaling and regulates the attraction of monocytic cells involved in the clearance of apoptotic neutrophils. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Attractive shedding Frank R. DeLeo Blood 2007 110: 1711-1712. [Full Text] [PDF] This article has been cited by other articles: L. Chen, A. Frister, S. Wang, A. Ludwig, H. Behr, S. Pippig, B. Li, A. Simm, B. Hofmann, C. Pilowski, et al. Interaction of vascular smooth muscle cells and monocytes by soluble factors synergistically enhances IL-6 and MCP-1 production Am J Physiol Heart Circ Physiol, April 1, 2009; 296(4): H987 - H996. [Abstract] [Full Text] [PDF] Y. Wang, A. H. Herrera, Y. Li, K. K. Belani, and B. Walcheck Regulation of Mature ADAM17 by Redox Agents for L-Selectin Shedding J. Immunol., February 15, 2009; 182(4): 2449 - 2457. [Abstract] [Full Text] [PDF] O. Islam, X. Gong, S. Rose-John, and K. Heese Interleukin-6 and Neural Stem Cells: More Than Gliogenesis Mol. Biol. Cell, January 1, 2009; 20(1): 188 - 199. [Abstract] [Full Text] [PDF] O. Soehnlein, A. Zernecke, E. E. Eriksson, A. G. Rothfuchs, C. T. Pham, H. Herwald, K. Bidzhekov, M. E. Rottenberg, C. Weber, and L. Lindbom Neutrophil secretion products pave the way for inflammatory monocytes Blood, August 15, 2008; 112(4): 1461 - 1471. [Abstract] [Full Text] [PDF] Y. Nechemia-Arbely, D. Barkan, G. Pizov, A. Shriki, S. Rose-John, E. Galun, and J. H. Axelrod IL-6/IL-6R Axis Plays a Critical Role in Acute Kidney Injury J. Am. Soc. Nephrol., June 1, 2008; 19(6): 1106 - 1115. [Full Text] [PDF] F. Walker, H.-H. Zhang, V. Matthews, J. Weinstock, E. C. Nice, M. Ernst, S. Rose-John, and A. W. Burgess IL6/sIL6R complex contributes to emergency granulopoietic responses in G-CSF- and GM-CSF-deficient mice Blood, April 15, 2008; 111(8): 3978 - 3985. [Abstract] [Full Text] [PDF] B. Rabe, A. Chalaris, U. May, G. H. Waetzig, D. Seegert, A. S. Williams, S. A. Jones, S. Rose-John, and J. Scheller Transgenic blockade of interleukin 6 transsignaling abrogates inflammation Blood, February 1, 2008; 111(3): 1021 - 1028. [Abstract] [Full Text] [PDF]

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