Interleukin 8, Neutrophil-Activating Peptide-2 and GRO-α Bind to and Elicit Cell Activation via Specific and Different Amino Acid Residues of CXCR2
Department of Periodontology, University of Tennessee, Memphis, TN, USA. Cytokine
(Impact Factor: 2.66).
11/2000; 12(10):1480-8. DOI: 10.1006/cyto.2000.0742
The objective of this investigation was to determine the amino acid residues of the human neutrophil CXC chemokine receptor-2 (CXCR2) that are critical for binding the ligands interleukin 8 (IL-8), neutrophil-activating peptide-2 (NAP-2), and growth-related protein alpha (GROalpha) and critical for receptor-mediated signal transduction. Charged residues of the amino terminus and the first extracellular loop of CXCR2 were targeted for point mutagenesis studies. Seven separate CXCR2 mutants (Glu7, Asp9, Glu12, Asp13, Lys108, Asn110, and Lys120, all to Ala) were generated. Based on the Scatchard analysis of radioligand binding studies, the following amino acids were deemed critical for ligand binding: (i) Asp9, Glu12, Lys108, and Lys120 for IL-8 and (ii) Glu7, Asp9, and Glu12 for GROalpha. Point mutations in the amino terminus domain (Asp9 and Glu12) and the first extracellular loop (Lys108, Asn110, and Lys120) of CXCR2 reduced cell activation to all three ligands as measured by changes in intracellular calcium concentration. In conclusion, high-affinity binding of IL-8, NAP-2, and GROalpha to CXCR2 involves interaction with specific and different amino acid residues of CXCR2. Furthermore, we propose that the CXCR2 amino acid residues required for cell activation are not necessarily the same residues required for ligand binding.
Available from: Robert H Miller
- "Chemokine receptors are G-protein coupled receptors (GPCRs) usually linked to pertussis toxin sensitive Gi proteins (Bajetto et al., 2001). The receptor CXCR2 is the primary mediator of signaling by the chemokine CXCL1 (Katancik et al., 2000), a soluble secreted chemoattractive molecule of the ELR family of CXC chemokines. Their interaction initiates intracellular processes that modulate a number of cellular events, including migration, proliferation, and differentiation (Bajetto et al., 2001; Miller, 2002; Tsai et al., 2002). "
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ABSTRACT: Multiple sclerosis (MS) is a neurodegenerative disease characterized by demyelination/remyelination episodes that ultimately fail. Chemokines and their receptors have been implicated in both myelination and remyelination failure. Chemokines regulate migration, proliferation and differentiation of immune and neural cells during development and pathology. Previous studies have demonstrated that the absence of the chemokine receptor CXCR2 results in both disruption of early oligodendrocyte development and long-term structural alterations in myelination. Histological studies suggest that CXCL1, the primary ligand for CXCR2, is upregulated around the peripheral areas of demyelination suggesting that this receptor/ligand combination modulates responses to injury. Here we show that in focal LPC-induced demyelinating lesions, localized inhibition of CXCR2 signaling reduced lesion size and enhanced remyelination while systemic treatments were relatively less effective. Treatment of spinal cord cultures with CXCR2 antagonists reduced CXCL1 induced A2B5+ cell proliferation and increased differentiation of myelin producing cells. More critically, treatment of myelin oligodendrocyte glycoprotein peptide 35-55-induced EAE mice, an animal model of multiple sclerosis, with small molecule antagonists against CXCR2 results in increased functionality, decreased lesion load, and enhanced remyelination. Our findings demonstrate the importance of antagonizing CXCR2 in enhancing myelin repair by reducing lesion load and functionality in models of multiple sclerosis and thus providing a therapeutic target for demyelinating diseases.
Available from: Amber E Kerstetter-Fogle
- "Chemokine receptors are Gprotein coupled receptors (GPCRs) usually linked to pertussis toxin sensitive Gi proteins (Bajetto et al., 2001). The receptor CXCR2 is the primary mediator of signaling by the chemokine CXCL1 (Katancik et al., 2000), a soluble secreted chemoattractive molecule of the glutamine-leucine-arginine (ELR) family of CXC chemokines. Their interaction initiates intracellular processes that modulate a number of cellular events, including migration, proliferation, and differentiation (Bajetto et al., 2001; Miller, 2002; Tsai et al., 2002). "
Available from: darwin.bth.rwth-aachen.de
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ABSTRACT: Tag der mündlichen Prüfung: 01.06.2010 Diese Dissertation ist auf den Internetseiten der Hochschulbibliothek online verfügbar.
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