CXCR2 stimulation primes CXCR1 [Ca2+]i responses to IL-8 in human neutrophils

Carl J. Hauser, Zoltan Fekete, Elliot R. Goodman, Eric Kleinstein, David H. Livingston, Edwin A. Deitch

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

Neutrophil (PMN) priming and subsequent responses to the IL-8 presented on pulmonary endothelial surfaces may be crucial determinants of the development of adult respiratory distress syndrome after injury. Elevated plasma ELR+ C-X-C chemokine (CXC) levels might contribute to PMN priming after trauma, but the role of CXCs in priming circulating PMNs is unstudied. We evaluated the interactions of IL-8 and GRO-α in priming human PMN calcium fluxes [Ca2+]i within circulatory environments. At physiologic concentrations, GRO-α primes PMN for IL-8 mediated [Ca2+]i mobilization, whereas IL-8 abolishes GRO-α responses. Repeated GRO-α exposures further enhance IL-8 responses. PMN priming for IL-8 responses in normal plasma was CXCR2 dependent. CXCR2 was more responsive than CXCR1 to low levels of IL-8, together suggesting that CXCR2 is the important CXC receptor at circulating (i.e., low) agonist concentrations. CXCR1 stimulation down-regulated CXCR2 surface expression, whereas CXCR2 stimulation upregulated CXCR1 expression. GRO-α / CXCR2 signaling enhanced post-receptor IL-8 initiated PMN [Ca2+]i influx as well as efflux. Sufficient stimulation of the CXCR1 terminated this cooperative relationship by down-regulating surface expression of CXCR2. This study is the first to report that at physiologic concentrations, C-X-C chemokines can act on circulating human PMNs as an integrated system where CXCR2 agonists, rather than cross-desensitizing CXCR1, act to enhance signaling of IL-8 at CXCR1 both by receptor and post-receptor mechanisms. Such CXCR2 mediated priming of CXCR1/ IL-8 interaction may enhance PMN attack on the lung after injury.

Original languageEnglish
Pages (from-to)428-437
Number of pages10
JournalShock
Volume12
Issue number6
DOIs
StatePublished - Dec 1999
Externally publishedYes

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