ALTERATIONS OF NEUTROPHIL RESPONSES TO TUMOR-NECROSIS-FACTOR-ALPHA AND INTERLEUKIN-8 FOLLOWING HUMAN ENDOTOXEMIA

Interleukin-8 (IL-8), a neutrophil chemoattractant and activating cyto kine, has been implicated as a proinflammatory mediator in gram-negati ve sepsis. In vitro data support the notion of IL-8 as an endothelial adherence inhibitor. To evaluate this issue, we infused six volunteers with reference endotoxin and measured plasma levels of IL-8, neutroph il tumor necrosis factor alpha (TNF-alpha) receptors, TNF-ru-induced a dherence to fibronectin, and neutrophil chemotaxis to IL-8 and other a ttractants. We found that, at 3 h postinfusion, IL-8 but not TNF-alpha plasma levels were elevated. Neutrophils had shed L-selectin (mean ch annel fluorescence decrease, 79 +/- 9 to 49 +/- 7; P = 0.0625) and TNF -alpha receptors (decrease in number of receptors per cell, 1,596 +/- 340 to 574 +/- 93; P = 0.004). Cells were chemotactically desensitized to IL-8. TNF-alpha-induced adherence to fibronectin was suppressed fr om 69% +/- 5% of the phorbol myristate acetate response to 38% +/- 7% (P = 0.0154). These findings support the notion that release of IL-8 i nto the vascular space may be an in vivo mechanism for suppression of neutrophil accumulation at extravascular sites. L-Selectin loss would reduce the ability of neutrophils to adhere to activated endothelial c ells. The specific loss of migratory response to IL-S would impair neu trophil delivery to areas where IL-8 was the predominant chemoattracta nt. Loss of TNF-alpha-induced adherence to fibronectin would blunt tho se responses, including production of oxidants, capacitated by adheren ce.