Blood, Vol 69. No 3 (March), 1987: pp 711-720 711 B L J #{128} D The American The Journal of Society of Hematology VOL 69, NO 3 MARCH 1987 REVIEW Protein Kinase C and the Activation of the Human Neutrophil NADPH-Oxidase By Alfred I.Tauber T HE NEUTROPHIL leads a short but dynamic life. Attuned to the vagaries ofsurveillance and destruction, it has developed a complex functional repertoire: Chemotax- is, adherence/aggregation, phagocytosis, degranulation, and oxidative burst require multi-component modes of response which, although highly integrated, may also be studied in dissected form. The problem of signal transduction is a major focus of current study in cell biology, and the neutro- phil has become a model of such inquiry, as attention to its various activities has discerned the outlines of its informa- tional response pathways. Within this context, I wish to review the current understanding of the activation mecha- nism of the respiratory burst enzyme, nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, as a paradigm of neutrophil secretory systems. This activity, defective in chronic granulomatous disease (CGD), is the principal defense against a wide variety of bacteria, and thus serves a crucial role in normal host defense.3’7 That a normal respira- tory burst is dependent on appropriate receptor function, intact activating pathways, and an integral NADPH-oxidase (which in itselfis multicomponent),7” predicts multiple sites at which a biochemical lesion may arrest the complex cascade. With recent studies in broken cell systems, impor- tant insights into the sequence ofactivation steps required for normal neutrophil response have been made. By tracing exogenous agonist-induced stimulation of the NADPH- oxidase, the basic elements of the activation sequence are now discerned. The human neutrophil has several well-defined receptors, including those for various components of C3,’2 immunoglo- bulin,’3 the formyl-methionyl (FMLP) bacterial peptides,’4 and leukotriene B4.’5 A recently described receptor is the ubiquitous protein kinase C (PK-C), a calcium, phospho- lipid-dependent kinase, activated by exogenous phorbol esters (eg, phorbol myristate acetate, PMA), and endoge- nously by diacyiglycerol liberated by the action of phospholi- pase or phosphodiesterase)6 The evidence that receptor- ligand binding is critical in the activation of the metabolic burst is the correlation between ligand binding and biochem- ical expression. A receptor-binding linkage to NADPH- oxidase activation for PMA has been established.’7 9 Patients with classically described CGD have not been reported to have abnormal receptor affinities as inferred by normal chemotactic and phagocytic responses3’8 or phorbol ester receptor binding,18 but certain patients have demon- strated selected responses to various stimuli and thus exhibit a defect in the activation apparatus2#{176}22; those with either congenital2’ or acquired defects3 in PMA-induced oxidase activation are of particular interest. Thus, CGD, which includes all defects of the oxidative metabolic effector sys- tem, may be divided into two types: abnormal activating mechanisms and abnormalities of NADPH-oxidase.3 The activation of the human neutrophil by PMA leads to a spectrum of responses, including aggregation,23 stimulation of the respiratory burst,’7 9’2 26 depolarization of the plasma membrane,27 enhanced phospholipid turnover,283#{176} and degranulation of specific granules.3’ The same constituent of the NADPH-oxidase found in the plasma membrane have been putatively reported in the specific granule membrane; upon PMA stimulation, a subset of these granules is translo-. cated to the plasma membrane, the site of the active respira- tory burst enZyme.32’33 Of the various stimulus-response- coupled functions defined for the normal neutrophil, I wish to focus on those biochemical phenomena related to the PMA receptor linked to the expression of NADPH-oxidase. In bypassing many associated complex metabolic activities, the PK-C system is a promising avenue for elucidating oxidase activation, at a site just proximal to the final expression of the respiratory burst enzyme. This PK-C dependent pathway is not the sole cascade for oxidase activation, however, since other soluble agonists and phagocytosed particles may bypass PK-C altogether.34’35 Although FMLP bypasses PK- C in elicited degranulation and oxidase activation, the che- motactic response is reduced by PK-C inhibition.3638 Defini- tion of parallel and cross-over points in the complex hierar- chy of the activation process have yet to be discerned, and there is only general acknowledgment that more than one activation pathway may generate an active oxidase. Recent studies have focused on the specificity of PMA for PK-C in eliciting a given biologic response. The synthetic diacylglycerol, I -oleoyl-2-acetylglycerol (OAG), directly From the William B. Castle Hematology Research Laboratory. Boston City Hospital, and the Departments of Medicine, Biochem- istry, and Pathology, Boston University School of Medicine. Supported in part by grants No. A120064 and HL33565from the National Institutes ofHealth, Bethesda, MD. Submitted April 4, 1986; accepted October 7, 1986. Address reprint requests to Dr Alfred I. Tauber, FGH-l, Boston City Hospital, Boston, MA 02! /8. © 1 987 by Grune & Stratton, Inc. 0006-4971/87/6903--000l$3.OO/O Downloaded from http://ashpublications.org/blood/article-pdf/69/3/711/594523/711.pdf by guest on 05 April 2022