Lipoxin A4 redistributes myosin IIA and Cdc42 in macrophages: implications for phagocytosis of apoptotic leukocytes
| Autor: | Catherine Godson, Keira Reville, John Crean, Ian Dransfield, Sharon Vivers |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Phagocytosis
Immunology Molecular Sequence Data Apoptosis Biology Glycogen Synthase Kinase 3 GSK-3 Leukocytes Immunology and Allergy Humans Protein phosphorylation Amino Acid Sequence Phosphorylation Protein kinase A cdc42 GTP-Binding Protein Protein kinase B Cells Cultured Protein Kinase C Glycogen Synthase Kinase 3 beta Macrophages Nonmuscle Myosin Type IIA Actin cytoskeleton Cell biology Lipoxins Cdc42 GTP-Binding Protein Proto-Oncogene Proteins c-akt |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 176(3) |
| ISSN: | 0022-1767 |
| Popis: | Lipoxins (LXs) are endogenously produced anti-inflammatory agents that modulate leukocyte trafficking and stimulate nonphlogistic macrophage phagocytosis of apoptotic neutrophils, thereby promoting the resolution of inflammation. Previous data suggest a role for altered protein phosphorylation and cytoskeletal rearrangement in LX-stimulated phagocytosis but the exact mechanisms remain unclear. In this study we examine the effects of LXA4 on the protein phosphorylation pattern of THP-1 cells differentiated into a macrophage-like phenotype. THP-1 cells stimulated with LXA4 (1 nM) exhibit dephosphorylation of a 220-kDa protein. Using mass spectrometry, this protein was identified as MYH9, a nonmuscle myosin H chain II isoform A, which is involved in cytoskeleton rearrangement. THP-1 cells treated with LXA4 adopt a polarized morphology with activated Cdc42 localized toward the leading edge and MYH9 localized at the cell posterior. Polarized distribution of Cdc42 is associated with Akt/PKB-mediated Cdc42 activation. Interestingly, the annexin-derived peptide Ac2–26, a recently described agonist for the LXA4 receptor, also stimulates macrophage phagocytosis, MYH9 dephosphorylation, and MYH9 redistribution. In addition, we demonstrate that LXA4 stimulates the phosphorylation of key polarity organization molecules: Akt, protein kinase Cζ, and glycogen synthase kinase-3β. Inhibition of LXA4-induced Akt and protein kinase Cζ activity with specific inhibitors prevented LXA4-stimulated phagocytosis of both apoptotic polymorphonuclear neutrophils and lymphocytes, highlighting a potential use for LXA4 in the treatment of autoimmune diseases. Furthermore, phosphorylation and subsequent inactivation of glycogen synthase kinase-3β resulted in an increase in phagocytosis similar to that of LXA4. These data highlight an integrated mechanism whereby LXA4 regulates phagocytosis through facilitative actin cytoskeleton rearrangement and cell polarization. |
| Databáze: | OpenAIRE |
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