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 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.
Address reprint requests to Carl J. Hauser MD, FACS, UMD / New Jersey Medical School, Department of Surgery, MSB G-524, 185 South Orange Avenue, Newark, NJ. 07103.
Received 31 March 1999; first review completed 22 Apr 1999; accepted in final form 21 May 1999
©1999The Shock Society