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Blood, 15 February 2002, Vol. 99, No. 4, pp. 1434-1441
PHAGOCYTES
Regulation of polymorphonuclear leukocyte degranulation and
oxidant production by ceramide through inhibition of phospholipase
D
Pamela J. Mansfield,
Vania Hinkovska-Galcheva,
Shannon S. Carey,
James A. Shayman, and
Laurence A. Boxer
From the Department of Pediatrics, Division of
Hematology/Oncology, and the Department of Internal Medicine, Division
of Nephrology, University of Michigan, Ann Arbor.
Exogenous C2-ceramide has been shown to inhibit
polymorphonuclear leukocyte (PMN) phagocytosis through inhibition of
phospholipase D (PLD) and downstream events, including activation of
extracellular signal-regulated kinases 1 and 2, leading to the
hyphothesis that the sphingomyelinase pathway is involved in
termination of phagocytosis. Here it is postulated that increased
PLD activity generating phosphatidic acid and diacylglycerol (DAG) is
essential for superoxide release and degranulation and that ceramide,
previously shown to be generated during PMN activation, inhibits PLD
activation, thereby leading to inhibition of PMN function. When PMNs
were primed with granulocyte colony-stimulating factor (G-CSF) and then
activated with N-formyl-methionyl-leucyl-phenylalanine (FMLP), C2-ceramide (10 µM) completely inhibited release
of superoxide, lactoferrin, and gelatinase; the DAG analog
sn-1,2-didecanoylglycerol (DiC10) (10 µM) restored
oxidase activation and degranulation in the ceramide-treated cells.
Similarly, C2-ceramide inhibited oxidase activity and
degranulation of PMNs treated with cytochalasin B followed by FMLP, and
DiC10 restored function. In contrast, C2-ceramide did not
inhibit phosphorylation of p47phox or p38 mitogen-activated protein
kinase, or translocation of p47phox, PLD-containing organelles,
adenosine diphosphate-ribosylation factor 1, RhoA, protein kinase C
(PKC)- or PKC- to the plasma membrane in G-CSF or cytochalasin
B-treated, FMLP-activated PMNs. PLD activity increased by 3-fold in
G-CSF-primed PMNs stimulated by FMLP and by 30-fold in cytochalasin
B-treated PMNs stimulated by FMLP. Both PLD activities were completely
inhibited by 10 µM C2-ceramide. In conclusion,
superoxide, gelatinase, and lactoferrin release require activation of
the PLD pathway in primed PMNs and cytochalasin B-treated PMNs.
Ceramide may affect protein interactions with PLD in the plasma
membrane, thereby attenuating PMN activation.
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