Cross-desensitization among CXCR1, CXCR2, and CCR5: Role of protein kinase C-ε

Mohd W. Nasser, Robin J. Marjoram, Stephan L. Brown, Ricardo M. Richardson

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31 Scopus citations

Abstract

The IL-8 (or CXCL8) chemokine receptors, CXCR1 and CXCR2, activate protein kinase C (PKC) to mediate leukocyte functions. To investigate the roles of different PKC isoforms in CXCL8 receptor activation and regulation, human mononuclear phagocytes were treated with CXCL8 or CXCL1 (melanoma growth-stimulating activity), which is specific for CXCR2. Plasma membrane association was used as a measure of PKC activation. Both receptors induced time-dependent association of PKCα, -β1, and -β2 to the membrane, but only CXCR1 activated PKCε. CXCL8 also failed to activate PKCε in RBL-2H3 cells stably expressing CXCR2. ΔCXCR2, a cytoplasmic tail deletion mutant of CXCR2 that is resistant to internalization, activated PKCε as well as CXCR1. Expression of the PKCε inhibitor peptide εV1 in RBL-2H3 cells blocked PKCε translocation and inhibited receptor-mediated exocytosis, but not phosphoinositide hydrolysis or peak intracellular Ca2+ mobilization. εV1 also inhibited CXCR1-, CCR5-, and ΔCXCR1-mediated cross-regulatory signals for GTPase activity, Ca2+ mobilization, and internalization. Peritoneal macrophages from PKCε-deficient mice (PKCε-/-) also showed decreased CCR5-mediated cross-desensitization of G protein activation and Ca2+ mobilization. Taken together, the results indicate that CXCR1 and CCR5 activate PKCε to mediate cross-inhibitory signals. Inhibition or deletion of PKCε decreases receptor-induced exocytosis and cross-regulatory signals, but not phosphoinositide hydrolysis or peak intracellular Ca2+ mobilization, suggesting that cross-regulation is a Ca2+-independent process. Because ΔCXCR2, but not CXCR2, activates PKCε and cross-desensitizes CCR5, the data further suggest that signal duration leading to activation of novel PKC may modulate receptor-mediated cross-inhibitory signals.

Original languageEnglish (US)
Pages (from-to)6927-6933
Number of pages7
JournalJournal of Immunology
Volume174
Issue number11
StatePublished - Jun 1 2005

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Nasser, M. W., Marjoram, R. J., Brown, S. L., & Richardson, R. M. (2005). Cross-desensitization among CXCR1, CXCR2, and CCR5: Role of protein kinase C-ε. Journal of Immunology, 174(11), 6927-6933.