POTENTIATION OF CHEMOTACTIC PEPTIDE-INDUCED SUPEROXIDE GENERATION BY CD38 LIGATION IN HUMAN MYELOID CELL-LINES

CD38 is a type II transmembrane glycoprotein possessing an NAD(+) glyc ohydrolase activity in its extracellular domain, We previously reporte d that the ligation of CD38 by a monoclonal antibody (mAb), HE-7, indu ces the tyrosine phosphorylation of cellular proteins including p120(c -cbl) in differentiated human myeloid cell lines and that the phosphor ylated p120(c-cbl) is capable of binding to phosphatidylinositol (PI) 3-kinase. In the present study, we found that the agonistic anti-CD38 mAb markedly potentiates superoxide generation stimulated by chemotact ic formyl-Met-Leu-Phe receptors in the CD38-producing cells, HE-7 neit her generated superoxide by itself nor enhanced the cell response indu ced by phorbol 12-myristate acetate, indicating that the potentiating action of the anti-CD38 mAb is specific for the stimulation by the GTP -binding protein (G(1))-coupled membrane receptors, The potentiation b y HE-7 was abolished by prior treatment of the cells with a tyrosine k inase inhibitor, pertussis toxin, or a potent PI 3-kinase inhibitor, w ortmannin. HE-7 also enhanced the product formation of PI 3-kinase in response to the chemotactic receptor stimulation, without significant changes in the receptor-stimulated accumulations of inositol-1,4,5-tri sphosphate, arachidonate release, and intracellular Ca2+. These result s indicate that the CD38-induced tyrosine phosphorylation has a crosst alk with the chemotactic receptor/G(i)-mediated signal transduction pa thway resulting in the enhancement of superoxide generation, probably through the activation of PI 3-kinase.