Different Signaling Pathways Stimulate a Disintegrin and Metalloprotease-17 (ADAM17) in Neutrophils during Apoptosis and Activation

• Published in: The Journal of biological chemistry 2011-11, Vol.286 (45), p.38980-38988
• Main Authors: Wang, Yue, Robertson, John D., Walcheck, Bruce
• Format: Article
• Language: English
• Subjects: ADAM; ADAM Proteins - genetics; ADAM Proteins - metabolism; ADAM17 Protein; Adhesion; Apoptosis; Apoptosis - physiology; Caspase 8 - genetics; Caspase 8 - metabolism; Cells, Cultured; Enzyme Activation - physiology; Enzyme Induction - physiology; Humans; Immunology; Inflammation; MAP Kinase Signaling System - physiology; Neutrophil; Neutrophil Activation - physiology; Neutrophils - cytology; Neutrophils - metabolism; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Receptors, Tumor Necrosis Factor, Type I - genetics; Receptors, Tumor Necrosis Factor, Type I - metabolism; Receptors, Tumor Necrosis Factor, Type II - genetics; Receptors, Tumor Necrosis Factor, Type II - metabolism; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.277087

ADAM17 is a membrane-associated metalloprotease that cleaves proteins from the surface of neutrophils and modulates the density of various receptors and adhesion molecules. The protease activity of ADAM17 is highly inducible and occurs upon neutrophil activation as well as apoptosis. At this time, little is known about the signal transduction pathway that promotes ADAM17 activity in neutrophils upon the induction of apoptosis. We show that caspase-8 activation, Bid cleavage, and the release of mitochondrial reactive oxygen species are sequential transduction components of the Fas signaling cascade that induces ADAM17. This is different from ADAM17 stimulation upon overt neutrophil activation, which requires MAPK p38 or ERK, but not caspases and reactive oxygen species. ADAM17 activity in apoptotic neutrophils may serve to inactivate select effector molecules that promote the pro-inflammatory activity of recruited neutrophils. For instance, TNFα receptors TNF-RI and TNF-RII are substrates of ADAM17, and we show that they are shed during apoptosis, decreasing neutrophil sensitivity to TNFα. Altogether, our findings provide significant new insights into the signal transduction pathway that stimulates ADAM17 during induced neutrophil apoptosis. ADAM17 induction during apoptosis may rapidly diminish neutrophil sensitivity to the inflammatory environment, complementing other anti-inflammatory activities by these cells during inflammation resolution. Background: Neutrophil ADAM17 (a disintegrin and metalloprotease-17) mediates the proteolytic release of receptors and soluble factors that regulate inflammation. Results: ADAM17 stimulation during Fas-induced neutrophil apoptosis requires caspase-8, Bid, and mitochondrial reactive oxygen species. Conclusion: Neutrophil ADAM17 stimulation occurs by different signal transduction pathways during activation and apoptosis. Significance: ADAM17 activation in apoptotic neutrophils may rapidly down-regulate their pro-inflammatory activity.