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Dissertation/Thesis Abstract

Disparate Regulation of Neutrophil Pro-Inflammatory Functioning by CXCR2-Selective Chemokines
by Williams, Mark Anthony, Ph.D., University of Cincinnati, 2000, 166; 10857373
Abstract (Summary)

The CXC subfamily of chemoattractant cytokines (chemokines) induce neutrophil migration to and activation at sites of infection or injury via two cell surface, G-protein coupled receptors (CXCR1 and CXCR2). CXCR1 binds interleukin 8 (IL-8) and granulocyte chemotactic peptide 2 (GCP-2), while CXCR2 additionally binds and responds to neutrophil activating peptide 2 (NAP-2), the growth related oncogene series (GROα, β and γ) and epithelial cell-derived neutrophil activator 78 (ENA-78) with high affinity. Compared to CXCR1, CXCR2 is preferentially desensitized and down-regulated following exposure to various proinflammatory stimulants and in neutrophils from patients suffering severe trauma or sepsis. These differences suggest that the CXC receptors perform subtype-specific functions.

The studies presented herein explored the general hypothesis that CXCR1 and CXCR2 perform specialized functions and that CXCR2-selective ligands differentially induced these responses. The role of IL-8 dimerization in mediating these specialized functions was also examined. The data indicate that IL-8-induced migration and suppression of the oxidative burst are mediated by CXCR1 and CXCR2, respectively, in human neutrophils. IL-8 must form a dimer to initiate CXCR2-mediated oxidative burst suppression, but not CXCR1-mediated chemotaxis.

Of the chemokines tested, only NAP-2 and IL-8 desensitized CXCR1-mediated migration. Radioligand binding and flow cytometric studies suggest that mechanisms other than CXC receptor down-regulation or affinity modulation are involved in chemotactic desensitization. Despite their equivalent high-affinity binding to CXCR2, the chemokines varied in their abilities to suppress the oxidative burst. Only IL-8, GCP-2 and GROα were effective in this assay. Additionally, they varied in their abilities to suppress the oxidative response to a range of stimuli. This suggests that the chemokines perturb the oxidase activation signaling pathway at different levels. The data support the conclusion that CXCR2-selective chemokines disparately regulate neutrophil proinflammatory functioning, despite their high affinity interactions with a single receptor. It is inferred that CXCR2, and possibly CXCR1, discriminates between high affinity agonists to activate agonist-specific signaling pathways responsible for chemotactic desensitzation and oxidative burst suppression. These data provide insights of a putative biologic role for secreting multiple chemokines, which selectively induce neutrophil responses. Furthermore, they implicate an anti-inflammatory role for chemokine dimer formation.

Indexing (document details)
Advisor: Solomkin, Joseph
School: University of Cincinnati
Department: Medicine : Molecular, Cellular and Biochemical Pharmacology
School Location: United States -- Ohio
Source: DAI-B 79/10(E), Dissertation Abstracts International
Subjects: Pharmacology
Keywords: Adherence, Chamotaxis, Dimarization, Oxidative burst, Receptor regulation
Publication Number: 10857373
ISBN: 978-0-438-03497-6
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