Chemokine regulation of neutrophil function in surgical inflammation.
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.


OBJECTIVE
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 alpha (TNF-alpha)-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-alpha-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.
Williams
M A
MA
Department of Surgery, University of Cincinnati College of Medicine, Ohio 45267-0558, USA.
Cave
C M
CM
Quaid
G
G
Solomkin
J S
JS
D054365:Chemokine CXCL5; D054427:Chemokine CXCL6; D018925:Chemokines / Q000502:physiology*; D019743:Chemokines, CXC / Q000097:blood; D006801:Humans; D016209:Interleukin-8 / Q000031:analogs & derivatives / Q000502:physiology; D020556:Neutrophil Infiltration / Q000276:immunology; D009504:Neutrophils / Q000276:immunology*; D010545:Peroxides / Q000378:metabolism; D011183:Postoperative Complications / Q000276:immunology*; D018746:Systemic Inflammatory Response Syndrome / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
C486263:CXCL5 protein, human; C515503:CXCL6 protein, human; D054365:Chemokine CXCL5; D054427:Chemokine CXCL6; D018925:Chemokines; D019743:Chemokines, CXC; D016209:Interleukin-8; D010545:Peroxides; D014409:Tumor Necrosis Factor-alpha