Postinjury suppression of human neutrophil cytokine production results from the stabilization of inhibitory kappa B

Postinjury neutrophil (PMN) dysfunction is a well recognized event that may be responsible for increased infections. PMN cytokine production is an imp ortant component of their bactericidal capacity. When PMNs are stimulated, inhibitory factor kappa B (I kappa B) is degraded, allowing nuclear factor kappa B (NF kappa B) to translocate to the nucleus and promotes genes for t he transcription of the interleukin-8 (IL-8) and tumor necrosis factor (TNF ) genes. We hypothesize that similar to their late postinjury depressed sup eroxide production, postinjury PMNs manifest suppressed cytokine production , which is mediated by stabilization of I kappa B levels. Methods: Twelve s everely injured patients with an injury severity score (ISS) of 24 (+/- 4.6 ) were studied as well as 10 elective surgical patients as a control. PMNs were isolated and incubated for 24 h in RPMI. PMNs were stimulated with lip opolysaccharide (LPS; 100 ng) or PAF (200 nm) and fMLP (1 mu M) and release of IL-8, TNF, and interleukin-l receptor antagonist (IL-1ra) were measured . Postinjury PMNs were also stimulated with LPS (100 ng), and I kappa B bre akdown was measured at 0, 30, and 60 min using gel electrophoresis. Results : Postinjury PMNs displayed a significant suppression of both IL-8 and TNF on postinjury Days 1-3, while the release of ii Ira was preserved throughou t the entire study period. In contrast, elective surgical patients demonstr ated no decrease in IL-8 or TNF. Furthermore, I kappa B levels were preserv ed in the postinjury PMNs as compared with normal control PMNs. Conclusion: Postinjury PMNs have a suppressed release of both IL-8 and TNF following i njury that dib not occur in elective surgical patients. Furthermore, the NF kappa B/I kappa B-independent IL-1ra did not show suppression of release. In addition, stabilization of I kappa B following severe injury leads to de creased PMN IL-8 and TNF production. This genetic reprogramming may help ex plain PMN dysfunction and subsequent infections seen in severely injured pa tients.