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Regulation of TNF‐induced oxygen radical production in human neutrophils: role of δ‐PKC

In human neutrophils, TNF‐elicited O2− production requires adherence and integrin activation. How this cooperative signaling between TNFRs and integrins regulates O2− generation has yet to be fully elucidated. Previously, we identified δ‐PKC as a critical early regulator of TNF signaling in adherent neutrophils. In this study, we demonstrate that inhibition of δ‐PKC with a dominant‐negative δ‐PKC TAT peptide resulted in a significant delay in the onset time of TNF‐elicited O2− generation but had no effect on Vmax, indicating an involvement of δ‐PKC in the initiation of O2− production. In contrast, fMLP‐elicited O2− production in adherent and nonadherent neutrophils was δ‐PKC‐independent, suggesting differential regulation of O2− production. An important step in activation of the NADPH oxidase is phosphorylation of the cytosolic p47phox component. In adherent neutrophils, TNF triggered a time‐dependent association of δ‐PKC with p47phox, which was associated with p47phox phosphorylation, indicating a role for δ‐PKC in regulating O2− production at the level of p47phox. Activation of ERK and p38 MAPK is also required for TNF‐elicited O2− generation. TNF‐mediated ERK but not p38 MAPK recruitment to p47phox was δ‐PKC‐dependent. δ‐PKC activity is controlled through serine/threonine phosphorylation, and phosphorylation of δ‐PKC (Ser643) and δ‐PKC (Thr505) was increased significantly by TNF in adherent cells via a PI3K‐dependent process. Thus, signaling for TNF‐elicited O2− generation is regulated by δ‐PKC. Adherence‐dependent cooperative signaling activates PI3K signaling, δ‐PKC phosphorylation, and δ‐PKC recruitment to p47phox. δ‐PKC activates p47phox by serine phosphorylation or indirectly through control of ERK recruitment to p47phox.