CXCR2 stimulation primes CXCR1 [Ca2+]i responses to IL-8 in human neutrophils.
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-alpha in priming human PMN calcium fluxes [Ca2+]i within circulatory environments. At physiologic concentrations, GRO-alpha primes PMN for IL-8 mediated [Ca2+]i mobilization, whereas IL-8 abolishes GRO-alpha responses. Repeated GRO-alpha 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-alpha/ 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 downregulating 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.
Hauser
C J
CJ
Department of Surgery, UMD-New Jersey Medical School, Newark 07103, USA.
Fekete
Z
Z
Goodman
E R
ER
Kleinstein
E
E
Livingston
D H
DH
Deitch
E A
EA
D000328:Adult; D015703:Antigens, CD / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects*; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8 / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D019707:Receptors, Chemokine / Q000187:drug effects* / Q000502:physiology; D018123:Receptors, Interleukin / Q000187:drug effects* / Q000502:physiology; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D012128:Respiratory Distress Syndrome / Q000503:physiopathology*
D015703:Antigens, CD; C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D019707:Receptors, Chemokine; D018123:Receptors, Interleukin; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D002118:Calcium