Daniel Dugi

School of Medicine, Urology

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

Garret Zallen; Ernest E. Moore; Jeffrey L. Johnson; Douglas Y. Tamura; Brian Shames; Walter L. Biffl; Christopher C. Silliman (Profiled Author: Garret Zallen)

Shock. 1999;11(2):77-81.

Postinjury neutrophil (PMN) dysfunction is a well recognized event that may be responsible for increased infections. PMN cytokine production is an important component of their bactericidal capacity. When PMNs are stimulated, inhibitory factor κB (IκB) is degraded, allowing nuclear factor κB (NFκB) to translocate to the nucleus and promotes genes for the transcription of the interleukin-8 (IL-8) and tumor necrosis factor (TNF) genes. We hypothesize that similar to their late postinjury depressed superoxide production, postinjury PMNs manifest suppressed cytokine production, which is mediated by stabilization of IκB levels. Methods: Twelve severely 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 lipopolysaccharide (LPS; 100 ng) or PAF (200 nm) and fMLP (1 μM) and release of IL-8, TNF, and interleukin-1 receptor antagonist (IL-1ra) were measured. Postinjury PMNs were also stimulated with LPS (100 ng), and κB breakdown 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 IL-1ra was preserved throughout the entire study period. In contrast, elective surgical patients demonstrated no decrease in IL-8 or TNF. Furthermore, IκB levels were preserved in the postinjury PMNs as compared with normal control PMNs. Conclusion: Postinjury PMNs have a suppressed release of both IL-8 and TNF following injury that did not occur in elective surgical patients. Furthermore, the NFκB/IκB-independent IL-1ra did not show suppression of release. In addition, stabilization of IκB following severe injury leads to decreased PMN IL-8 and TNF production. This genetic reprogramming may help explain PMN dysfunction and subsequent infections seen in severely injured patients.

PMID: 10030791    

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