CCR1-Mediated STAT3 Tyrosine Phosphorylation and CXCL8 Expression in THP-1 Macrophage-like Cells Involve Pertussis Toxin-Insensitive Gα14/16 Signaling and IL-6 Release
| Autor: | Maggie M. K. Lee, Alaster H. Y. Lau, Issan Yee San Tam, Ricky K. S. Chui, Yung Hou Wong |
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| Rok vydání: | 2012 |
| Předmět: |
STAT3 Transcription Factor
G protein medicine.medical_treatment Immunology Receptors CCR1 Gene Expression Biology Transfection Pertussis toxin Antibodies chemistry.chemical_compound Cytosol Serine medicine Humans Protein Isoforms Immunology and Allergy Phosphorylation Cell Nucleus Interleukin-6 Macrophages Interleukin-8 HEK 293 cells Tyrosine phosphorylation Macrophage Inflammatory Proteins Molecular biology HEK293 Cells Cytokine Pertussis Toxin chemistry Chemokines CC GTP-Binding Protein alpha Subunits Gq-G11 Tyrosine K562 Cells Plasmids Signal Transduction K562 cells |
| Zdroj: | The Journal of Immunology. 189:5266-5276 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | Agonists of CCR1 contribute to hypersensitivity reactions and atherosclerotic lesions, possibly via the regulation of the transcription factor STAT3. CCR1 was demonstrated to use pertussis toxin-insensitive Gα14/16 to stimulate phospholipase Cβ and NF-κB, whereas both Gα14 and Gα16 are also capable of activating STAT3. The coexpression of CCR1 and Gα14/16 in human THP-1 macrophage-like cells suggests that CCR1 may use Gα14/16 to induce STAT3 activation. In this study, we demonstrated that a CCR1 agonist, leukotactin-1 (CCL15), could indeed stimulate STAT3 Tyr705 and Ser727 phosphorylation via pertussis toxin-insensitive G proteins in PMA-differentiated THP-1 cells, human erythroleukemia cells, and HEK293 cells overexpressing CCR1 and Gα14/16. The STAT3 Tyr705 and Ser727 phosphorylations were independent of each other and temporally distinct. Subcellular fractionation and confocal microscopy illustrated that Tyr705-phosphorylated STAT3 translocated to the nucleus, whereas Ser727-phosphorylated STAT3 was retained in the cytosol after CCR1/Gα14 activation. CCL15 was capable of inducing IL-6 and IL-8 (CXCL8) production in both THP-1 macrophage-like cells and HEK293 cells overexpressing CCR1 and Gα14/16. Neutralizing Ab to IL-6 inhibited CCL15-mediated STAT3 Tyr705 phosphorylation, whereas inhibition of STAT3 activity abolished CCL15-activated CXCL8 release. The ability of CCR1 to signal through Gα14/16 provides a linkage for CCL15 to regulate IL-6/STAT3–signaling cascades, leading to expression of CXCL8, a cytokine that is involved in inflammation and the rupture of atherosclerotic plaque. |
| Databáze: | OpenAIRE |
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