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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.

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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.


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