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Selective regulation by delta-PKC and PI 3-kinase in the assembly of the antiapoptotic TNFR-1 signaling complex in neutrophils
Authors:Kilpatrick Laurie E  Sun Shuang  Korchak Helen M
Institution:Immunology Section, Rm. 1212H Abramson Bldg., Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA. kilpatrick@email.chop.edu
Abstract:TNF is implicated in the attenuation of neutrophil constitutive apoptosis during sepsis. Antiapoptotic signaling is mediated principally through the TNF receptor-1 (TNFR-1). In adherent neutrophils, when {beta}-integrin signaling is activated, TNF phosphorylates TNFR-1 and activates prosurvival and antiapoptotic signaling. Previously, we identified the {delta}-PKC isotype and phosphatidylinositol (PI) 3-kinase as critical regulators of TNF signaling in adherent neutrophils. Both kinases associate with TNFR-1 in response to TNF and are required for TNFR-1 serine phosphorylation, NF-{kappa}B activation, and inhibition of apoptosis. The purpose of this study was to examine the role of {delta}-PKC and PI 3-kinase in the assembly of TNFR-1 signaling complex that regulates NF-{kappa}B activation and antiapoptotic signaling. Coimmunoprecipitation studies established that PI 3-kinase, {delta}-PKC, and TNFR-1 formed a signal complex in response to TNF. {delta}-PKC recruitment required both {delta}-PKC and PI 3-kinase activity, whereas PI 3-kinase recruitment was {delta}-PKC independent, suggesting that PI 3-kinase acts upstream of {delta}-PKC. An important regulatory step in control of antiapoptotic signaling is the assembly of the TNFR-1-TNFR-1-associated death domain protein (TRADD)-TNFR-associated factor 2 (TRAF2)-receptor interacting protein (RIP) complex that controls NF-{kappa}B activation. Inhibition of either {delta}-PKC or PI 3-kinase decreased TNF-mediated recruitment of RIP and TRAF2 to TNFR-1. In contrast, TRADD recruitment was enhanced. Thus {delta}-PKC and PI 3-kinase are positive regulators of TNF-mediated association of TRAF2 and RIP with TNFR-1. Conversely, these kinases are negative regulators of TRADD association. These results suggest that {delta}-PKC and PI 3-kinase regulate TNF antiapoptotic signaling at the level of the TNFR-1 through control of assembly of a TNFR-1-TRADD-RIP-TRAF2 complex. inflammation; tumor necrosis factor receptor-1-associated death domain protein; receptor interacting protein; tumor necrosis factor receptor-associated factor 2; antiapoptotic signaling
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