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,
*
Department of Pathology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA 19104; and Departments of
Medicine and
Immunology, Duke University Medical Center, Durham, NC 27710
Chemoattractants are thought to be the first mediators generated at
sites of bacterial infection. We hypothesized that signaling through G
protein-coupled chemoattractant receptors may stimulate cytokine
production. To test this hypothesis, a human mast cell line (HMC-1)
that normally expresses receptors for complement components C3a and C5a
at low levels was stably transfected to express physiologic levels of
fMLP receptors. We found that fMLP, but not C3a or C5a, induced
macrophage inflammatory protein (MIP)-1ß (CCL4) and monocyte
chemoattractant protein-1 (CCL2) mRNA and protein. Although fMLP
stimulated both sustained Ca2+ mobilization and
phosphorylation of extracellular signal-regulated kinase (ERK), these
responses to C3a or C5a were transient. However, transient expression
of C3a receptors in HMC-1 cells rendered the cells responsive to C3a
for sustained Ca2+ mobilization and MIP-1ß production.
The fMLP-induced chemokine production was blocked by pertussis toxin,
PD98059, and cyclosporin A, which respectively inhibit
Gi
activation, mitgen-activated protein kinase
kinase-mediated ERK phosphorylation, and calcineurin-mediated
activation of NFAT. Furthermore, fMLP, but not C5a, stimulated NFAT
activation in HMC-1 cells. These data indicate that chemoattractant
receptors induce chemokine production in HMC-1 cells with a selectivity
that depends on the level of receptor expression, the length of their
signaling time, and the synergistic interaction of multiple signaling
pathways, including extracellular signal-regulated kinase
phosphorylation, sustained Ca2+ mobilization and NFAT
activation.
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