Chemotactic agents induce IL-6Ralpha shedding from polymorphonuclear cells: involvement of a metalloproteinase of the TNF-alpha-converting enzyme (TACE) type.
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-alpha (IL-6Ralpha, 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-6Ralpha membrane expression and increased soluble IL-6Ralpha concentrations in the neutrophil supernatants, consistent with a shedding process. IL-6Ralpha shedding involved a TNF-alpha-converting enzyme-type metalloproteinase since it was partly decreased in the presence of a specific inhibitor, but not cathepsin G since PMSF or alpha1 antichymotrypsin had no effect. Neutrophil IL-6Ralpha 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.
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D056649:Cathepsin G; D002403:Cathepsins / Q000502:physiology; D002630:Chemotactic Factors / Q000494:pharmacology*; D004151:Dipeptides / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D016209:Interleukin-8 / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000502:physiology*; D009504:Neutrophils / Q000502:physiology*; D010972:Platelet Activating Factor / Q000494:pharmacology; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D012697:Serine Endopeptidases
D002630:Chemotactic Factors; D004151:Dipeptides; D006877:Hydroxamic Acids; D016209:Interleukin-8; C092152:N-((2-(hydroxyaminocarbonyl)methyl)-4-methylpentanoyl)-3-(2'-naphthyl)alanylalanine, 2-aminoethylamide; D010972:Platelet Activating Factor; D019947:Receptors, Interleukin-6; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human