Increased monocyte TNF-alpha message stability contributes to trauma patients' increased TNF production

Post-trauma elevation of tumor necrosis factor alpha (TNF-alpha) appears to be critical in mediating many symptoms of systemic inflammatory response syndrome (SIRS), resulting in late mortality, Although increased monocyte (m phi)) TNF-alpha production plays a pivotal role in this TNF-alpha elevation, the molecular mechanisms leading to increased m phi TNF-alpha production have yet to be elucidated, We demonstrate that, although TNF-alpha mRNA levels are increased in all trauma patients' m phi, which produce elevated levels of TNF-alpha protein, in the majority of patients, these increased TNF-alpha mRNA levels are under normal transcriptional and posttranscriptional control. Consequently, the increased TNF-alpha production by these patients' m phi is probably due to preactivation of these m phi by trauma-released mediators. However, a small minority of patients, whose mortality rate Teas 57%, produce TNF-alpha of primarily the membrane-associated type, The m phi TNF-alpha mRNA accumulation of these patients in response to in vitro stimulation is significantly augmented, All of these patients experienced SIRS, In this subset of patients' m phi, TNF-alpha mRNA stability was aberrantly increased, Such an increase in TNF-alpha mRNA stability could lead to devastatingly prolonged production of TNF-alpha protein, This demonstration of increased TNF-alpha mRNA stability in post-trauma m phi represents a novel correlation of elevated membrane-associated TNF-alpha protein, increased mortality, and a mechanism for this occurrence.