Abstract
CCL3 (MIP-1alpha), a prototype of CC chemokines, is a potent chemoattractant toward human neutrophils pre-treated with GM-CSF for 15 min. GM-CSF-treated neutrophils migrate also to the selective CCR5 agonist CCL4 (MIP-1beta). CCL3- and CCL4-triggered migration of GM-CSF-primed neutrophils was inhibited by the CCR5 antagonist TAK-779. Accordingly, freshly isolated neutrophils express CCR5. Extracellular signal-regulated kinases (ERK)-1/2 and p38 mitogen-activated protein kinase (MAPK) inhibitors blocked CCL3-induced migration of GM-CSF-primed neutrophils. When the activation of ERK-1/2 and p38 MAPK by CCL3 and the classical neutrophilic chemokine CXCL8 (IL-8) were compared, both the chemokines were capable of activating p38 MAPK. On the contrary, whereas both ERK-1 and ERK-2 were activated by CXCL8, no ERK-1 band was detectable after CCL3 triggering. Finally, neutrophil pre-treatment with GM-CSF activated both ERK-1 and ERK-2. This suggests that by activating ERK-1, GM-CSF renders neutrophils rapidly responsive to CCL3 stimulation throughout CCR5 which is constitutively expressed on the cell surface.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amides / pharmacology
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CCR5 Receptor Antagonists
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Cell Membrane / metabolism
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Chemokine CCL3
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Chemokine CCL4
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Chemotaxis, Leukocyte*
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Enzyme Activation
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Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
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Granulocyte-Macrophage Colony-Stimulating Factor / physiology*
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Humans
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In Vitro Techniques
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Interleukin-8 / metabolism
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Macrophage Inflammatory Proteins / metabolism*
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Mitogen-Activated Protein Kinase 3 / metabolism*
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Neutrophils / drug effects
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Neutrophils / metabolism
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Neutrophils / physiology*
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Quaternary Ammonium Compounds / pharmacology
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Receptors, CCR5 / physiology*
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Signal Transduction
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p38 Mitogen-Activated Protein Kinases / metabolism
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src-Family Kinases / metabolism
Substances
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Amides
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CCR5 Receptor Antagonists
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Chemokine CCL3
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Chemokine CCL4
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Interleukin-8
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Macrophage Inflammatory Proteins
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Proto-Oncogene Proteins
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Quaternary Ammonium Compounds
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Receptors, CCR5
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Granulocyte-Macrophage Colony-Stimulating Factor
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TAK 779
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src-Family Kinases
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase 3
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p38 Mitogen-Activated Protein Kinases