Wang et al.
Dec 1, 2001
This study investigates the role of tyrosine phosphorylation in the ligand-independent sequestration of the CXCR4 receptor in human primary monocytes-macrophages.
This study investigates the role of tyrosine phosphorylation in the ligand-independent sequestration of the CXCR4 receptor in human primary monocytes-macrophages. CXCR4 is crucial in immune cell trafficking and HIV-1 infection, particularly as a coreceptor for HIV. The study explores how cytokines, such as IL-4, IL-13, and GM-CSF, modulate CXCR4 expression and function through tyrosine phosphorylation.
Key findings include:
Cytokine Effects on CXCR4: IL-4, IL-13, and GM-CSF significantly down-regulated surface CXCR4 expression on monocytes, while other cytokines like IL-10 and TGF-β1 upregulated it. This regulation occurred without changes in CXCR4 mRNA or total protein levels, suggesting post-translational modification.
Tyrosine Phosphorylation: Cytokines triggered tyrosine phosphorylation of CXCR4, a key step in receptor sequestration. Inhibition of tyrosine kinase activity (using herbimycin A) reversed the down-regulation, indicating that tyrosine phosphorylation is essential for cytokine-induced CXCR4 sequestration.
Role of GRK3 and FAK: Cytokines like GM-CSF upregulated the expression of GRK3 (G protein-coupled receptor kinase) and FAK (focal adhesion kinase), which are involved in CXCR4 phosphorylation and sequestration, supporting the idea that these kinases contribute to CXCR4 regulation.
Impact on HIV-1 Infection: The study also shows that cytokines can inhibit HIV-1 infection by modulating CXCR4 expression and function. Specifically, GM-CSF, IL-4, and IL-13 reduced macrophage susceptibility to infection by X4 HIV-1 isolates.
Overall, the study highlights the role of tyrosine phosphorylation in the cytokine-mediated regulation of CXCR4 and its implications for immune function and HIV-1 infection. This process could be targeted for therapeutic strategies in HIV and related diseases.