Chemotactic agents induce IL-6Rα shedding from polymorphonuclear cells: involvement of a metalloproteinase of the TNF-α-converting enzyme (TACE) type

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Abstract
Interleukin (IL)-6 transsignaling plays a pivotal role in the shift from neutrophil to monocyte recruitment at the inflammatory site. Release of neutrophil IL-6 receptor-α (IL-6Rα, CD126) in its soluble form is a key step of IL-6 transsignaling, however, its physiological inducers are poorly known. Here, we observed that the neutrophil chemoattractants IL-8, C5a complement fraction, platelet activating factor, leukotriene B4 and N-formyl-methionyl-leucyl-phenylalanine rapidly decreased IL-6Rα membrane expression and increased soluble IL-6Rα concentrations in the neutrophil supernatants, consistent with a shedding process. IL-6Rα shedding involved a TNF-α-converting enzyme-type metalloproteinase since it was partly decreased in the presence of a specific inhibitor, but not cathepsin G since PMSF or α1 antichymotrypsin had no effect. Neutrophil IL-6Rα shedding may be a common feature of neutrophilic infiltrates in various inflammatory situations, allowing IL-6 transsignaling, decreasing neutrophil infiltration and in the meantime favoring monocyte recruitment, thus the initiation of an immune response and subsequently the resolution of inflammation.

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