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Blood, Vol. 93 No. 2 (January 15), 1999:
pp. 686-693
Sphingosine Blocks Human Polymorphonuclear Leukocyte Phagocytosis
Through Inhibition of Mitogen-Activated Protein Kinase Activation
Evelin M.B. Raeder,
Pamela J. Mansfield,
Vania Hinkovska-Galcheva,
Lars Kjeldsen,
James A. Shayman, and
Laurence A. Boxer
From the Department of Pediatrics, Division of Hematology/Oncology,
and Department of Internal Medicine, Division of Nephrology, University
of Michigan, Ann Arbor, MI.
In the present study, we investigated the mechanism by which
sphingosine and its analogues, dihydrosphingosine and phytosphingosine, inhibit polymorphonuclear leukocyte (PMN) phagocytosis of IgG-opsonized erythrocytes (EIgG) and inhibit ERK1 and ERK2 phosphorylation. We used
antibodies that recognized the phosphorylated forms of ERK1 (p44) and
ERK2 (p42) (extracellular signal-regulated protein kinases 1 and 2).
Sphingoid bases inhibited ERK1 and ERK2 activation and phagocytosis of
EIgG in a concentration-dependent manner. Incubation with glycine,
N,N -[1,2-ethanediylbis(oxy-2,1-phenylene)]bis[N-[2-[(acetyloxy)methoxy]-2-oxoethyl]]-bis[(acetyloxy)methyl]ester (BAPTA,AM), an intracellular chelator of calcium, failed to block either phagocytosis or ERK1 and ERK2 phosphorylation, consistent with
the absence of a role for a calcium-dependent protein kinase C (PKC) in
ERK1 and ERK2 phosphorylations. Western blotting demonstrated that
sphingosine inhibited the translocation of Raf-1 and PKC from PMN
cytosol to the plasma membrane during phagocytosis. These data are
consistent with the interpretation that sphingosine regulates ERK1 and
ERK2 phosphorylation through inhibition of PKC, and this in turn
leads to inhibition of Raf-1 translocation to the plasma membrane.
Consistent with this interpretation, the sphingosine-mediated inhibition of phagocytosis, ERK2 activation, and PKC translocation to the plasma membrane could be abrogated with a cell-permeable diacylglycerol analog. The increase in the diacylglycerol mass correlated with the translocation of PKC and Raf-1 to the plasma membrane by 3 minutes after the initiation of phagocytosis.
Additionally, the diacylglycerol analog enhanced phagocytosis by
initiating activation of PKC and its translocation to the plasma
membrane. Because PMN generate sufficient levels of sphingosine by 30 minutes during phagocytosis of EIgG to inhibit phagocytosis, it appears that sphingosine can serve as an endogenous regulator of EIgG-mediated phagocytosis by downregulating ERK activation.
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