Rac2 regulates specific signaling pathways which activates neutrophil NADPH oxidase

초록

Rac2 is a hematopoietic-specific Rho-family GTPase and Rac2-deficiency displayed significant defects in neutrophil functions (Immunity 10: 183-196, 1999). PMA induced superoxide production by rac-/- neutrophils was significantly reduced, but was near normal in neutrophils primed with TNF-a. Arachidonic acid fully restored PMA-elicited superoxide production, whereas arachidonic acid alone did not rescue superoxide production. Superoxide production in rac2-/- neutrophils was normal in response to opsonized zymosan (OpZ), reduced to 22% of wild-type in response to IgG-coated sheep red blood cells (IgG-SRBC), and almost absent in response to FMLP. In wild-type neutrophils, PMA or FMLP induced phosphorylation of ERK1/2, p38 MAP kinase, JNK and Akt, and ERK1/2 and p38 phosphorylation was decreased in rac2-/- neutrophils. Activation of p38 by either OpZ or IgG-SRBC was similar in wild-type and rac2-/- cells. Inhibition of ERK1/2 or p38 activation using either PD98059 or SB203580, respectively, had only a modest effect on FMLP-elicited superoxide production and no effect on the PMA-induced response. Rac2 plays a stimulus-specific role in regulating NADPH oxidase activation in neutrophils, particulary those downstream of chemoattractant and Fc-gamma receptors.