Differential activation and regulation of CXCR1 and CXCR2 by CXCL8 monomer and dimer

Mohd W. Nasser, Sandeep K. Raghuwanshi, Delores J. Grant, Venkatakrishna R. Jala, Krishna Rajarathnam, Ricardo M. Richardson

Research output: Contribution to journalArticle

100 Scopus citations

Abstract

CXCL8 (also known as IL-8) activates CXCR1 and CXCR2 to mediate neutrophil recruitment and trigger cytotoxic effect at sites of infection. Under physiological conditions, CXCL8 could exist as monomers, dimers, or a mixture of monomers and dimers. Therefore, both forms of CXCL8 could interact with CXCR1 and CXCR2 with different affinities and potencies to mediate different cellular responses. In the present study, we have used a "trapped" nonassociating monomer (L25NMe) and a nondissociating dimer (R26C) to investigate their activities for human neutrophils that express both receptors and for RBL-2H3 cells stably expressing either CXCR1(RBL-CXCR1) or CXCR2 (RBL-CXCR2). The monomer was more active than the dimer for activities such as intracellular Ca2+ mobilization, phosphoinositide hydrolysis, chemotaxis. and exocytosis. Receptor regulation, however, is distinct for each receptor. The rate of monomer-mediated regulation of CXCR1 is greater for activities such as phosphorylation, desensitization, β-arrestin translocation, and internalization. In contrast, for CXCR2, both monomeric and dimeric CXCL8 mediate these activities to a similar extent. Interestingly, receptor-mediated signal-regulated kinase (ERK) phosphorylation in response to all three CXCL8 variants was more sustained for CXCR2 relative to CXCR1. Taken together, the results indicate that the CXCL8 monomer and dimer differentially activate and regulate CXCR1 and CXCR2 receptors. These distinct properties of the ligand and the receptors play a critical role in orchestrating neutrophil recruitment and eliciting cytotoxic activity during an inflammatory response.

Original languageEnglish (US)
Pages (from-to)3425-3432
Number of pages8
JournalJournal of Immunology
Volume183
Issue number5
DOIs
StatePublished - Sep 1 2009

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint Dive into the research topics of 'Differential activation and regulation of CXCR1 and CXCR2 by CXCL8 monomer and dimer'. Together they form a unique fingerprint.

  • Cite this

    Nasser, M. W., Raghuwanshi, S. K., Grant, D. J., Jala, V. R., Rajarathnam, K., & Richardson, R. M. (2009). Differential activation and regulation of CXCR1 and CXCR2 by CXCL8 monomer and dimer. Journal of Immunology, 183(5), 3425-3432. https://doi.org/10.4049/jimmunol.0900305