Chemokine regulation of neutrophil function in surgical inflammation

Background: Morbidity and even mortality correlate closely with major injur y that causes a systemic inflammatory response. Cytokines and bioactive mol ecules present at the inflammatory sire induce this response and regulate n eutrophil proinflammatory responses. The CXC chemokines, important for neut rophil recruitment and activation, include interleukin 8 (IL-8), granulocyt e chemotactic protein 2 (GCP-2), and epithelial cell-derived neutrophil att ractant 78 (ENA-78). They induce neutrophil responses via 2 cell-surface re ceptors, CXCR-1 and CXCR-2. All 3 chemokines bind CXCR-2 with high affinity . Only IL-8 and GCP-2 bind CXCR-1 with high affinity. Hypothesis: The CXC chemokines regulate neutrophil responses differently. Methods: Pretreatment of neutrophils from healthy volunteers with IL-8, GCP -2, or ENA-78; measured IL-8 induced migration; and tumor necrosis factor a lpha (TNF-alpha)-induced peroxide production. Results: Flow cytometry and radioligand binding data indicate that IL-8, GC P-2, and ENA-78 equivalently reduced CXCR-1 and CXCR-2 cell surface express ion by 34% to 54%. All treatments decreased affinity of both receptors 1.5- to 2-fold. However, only IL-8 pretreatment inhibited chemotaxis to 10-nmol /L IL-8 (mean +/- SE inhibition, 62% +/- 6%). Although IL-8 and GCP-2, but not ENA-78, suppressed TNF-alpha-induced oxidant production (mean +/- SE in hibition, 42% +/- 8% and 40% +/- 23%, respectively), only GCP-2 inhibited t he oxidative response to complement fragment C5a, and to the bacterial cell wall peptide N-formyl-methionyl-leucylphenylalanine. Conclusions: The CXC chemokines regulate neutrophil proinflammatory functio ns differently. A thorough understanding of mechanisms for modulating neutr ophil responses in inflammation will aid the development of interventions t hat reduce morbidity and mortality associated with severe trauma and sepsis .