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* Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707; and Department of Biochemistry, Meharry Medical College, Nashville, TN 37208
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 PKC
, -
1, and -2 to the membrane, but only CXCR1 activated PKC
. CXCL8 also failed to activate PKC in RBL-2H3 cells stably expressing CXCR2. 
CXCR2, a cytoplasmic tail deletion mutant of CXCR2 that is resistant to internalization, activated PKC as well as CXCR1. Expression of the PKC inhibitor peptide V1 in RBL-2H3 cells blocked PKC translocation and inhibited receptor-mediated exocytosis, but not phosphoinositide hydrolysis or peak intracellular Ca2+ mobilization. V1 also inhibited CXCR1-, CCR5-, and CXCR2-mediated cross-regulatory signals for GTPase activity, Ca2+ mobilization, and internalization. Peritoneal macrophages from PKC-deficient mice (PKC–/–) also showed decreased CCR5-mediated cross-desensitization of G protein activation and Ca2+ mobilization. Taken together, the results indicate that CXCR1 and CCR5 activate PKC to mediate cross-inhibitory signals. Inhibition or deletion of PKC 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 CXCR2, but not CXCR2, activates PKC and cross-desensitizes CCR5, the data further suggest that signal duration leading to activation of novel PKC may modulate receptor-mediated cross-inhibitory signals.
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