Functional coupling of Fc gamma RI to nicotinamide adenine dinucleotide phosphate (reduced form) oxidative burst and immune complex trafficking requires the activation of phospholipase D1
Aj. Melendez et al., Functional coupling of Fc gamma RI to nicotinamide adenine dinucleotide phosphate (reduced form) oxidative burst and immune complex trafficking requires the activation of phospholipase D1, BLOOD, 98(12), 2001, pp. 3421-3428
Immunoglobulin G (IgG) receptors (Fc gamma Rs) on myeloid cells are respons
ible for the internalization of immune complexes. Activation of the oxidase
burst is an important component of the integrated cellular response mediat
ed by Fc receptors. Previous work has demonstrated that, in interferon-gamm
a -primed U937 cells, the high-affinity receptor for IgG, Fc gamma RI, is c
oupled to a novel intracellular signaling pathway that involves the sequent
ial activation of phospholipase D (PLD), sphingosine kinase, and calcium tr
ansients. Here, it is shown that both known PLD isozymes, PLD1 and PLD2, we
re present in these cells. With the use of antisense oligonucleotides to sp
ecifically reduce the expression of either isozyme, PLD1, but not PLD2, was
found to be coupled to Fc gamma RI activation and be required to mediate r
eceptor activation of sphingosine kinase and calcium transients. In additio
n, coupling of Fc gamma RI to activation of the nicotinamide adenine dinucl
eotide phosphate (reduced form) (NADPH) oxidase burst was inhibited by pret
reating cells with 0.3% butan-1-ol, indicating an absolute requirement for
PLD. Furthermore, use of antisense oligonucleotides to reduce expression of
PLD1 or PLD2 demonstrated that PLD1 is required to couple Fc gamma RI to t
he activation of NADPH oxidase and trafficking of internalized immune compl
exes for degradation. These studies demonstrate the critical role of PLD1 i
n the intracellular signaling cascades initiated by Fc gamma RI and its fun
ctional role in coordinating the response to anti gen-anti body complexes.
(Blood. 2001;98:3421-3428) (C) 2001 by The American Society of Hematology.