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Mark A. Williams; Cindy M. Cave; Gina Quaid, MD; Joseph S. Solomkin, MD

Arch Surg. 1999;134:1360-1366.

Background  Morbidity and even mortality correlate closely with major injury that causes a systemic inflammatory response. Cytokines and bioactive molecules present at the inflammatory site induce this response and regulate neutrophil proinflammatory responses. The CXC chemokines, important for neutrophil recruitment and activation, include interleukin 8 (IL-8), granulocyte chemotactic protein 2 (GCP-2), and epithelial cell-derived neutrophil attractant 78 (ENA-78). They induce neutrophil responses via 2 cell-surface receptors, 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 (TNF-)–induced peroxide production.

Results  Flow cytometry and radioligand binding data indicate that IL-8, GCP-2, and ENA-78 equivalently reduced CXCR-1 and CXCR-2 cell surface expression 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-–induced oxidant production (mean ± SE inhibition, 42% ± 8% and 40% ± 23%, respectively), only GCP-2 inhibited the oxidative response to complement fragment C5a, and to the bacterial cell wall peptide N-formyl-methionyl-leucyl-phenylalanine.

Conclusions  The CXC chemokines regulate neutrophil proinflammatory functions differently. A thorough understanding of mechanisms for modulating neutrophil responses in inflammation will aid the development of interventions that reduce morbidity and mortality associated with severe trauma and sepsis.

From the Departments of Surgery (Mr Williams, Ms Cave, and Drs Quaid and Solomkin) and Pharmacology and Cell Biophysics (Mr Williams and Dr Solomkin), University of Cincinnati College of Medicine, Cincinnati, Ohio.

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