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 (mphi) TNF-alpha production plays a pivotal role in this TNF-alpha elevation, the molecular mechanisms leading to increased mphi TNF-alpha production have yet to be elucidated. We demonstrate that, although TNF-alpha mRNA levels are increased in all trauma patients' mphi, 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' mphi is probably due to preactivation of these mphi by trauma-released mediators. However, a small minority of patients, whose mortality rate was 57%, produce TNF-alpha of primarily the membrane-associated type. The mphi 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' mphi, 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 mphi represents a novel correlation of elevated membrane-associated TNF-alpha protein, increased mortality, and a mechanism for this occurrence.
Furse
R K
RK
University of Massachusetts Medical Center, Department of Surgery, Worcester 01655, USA.
Kodys
K
K
Zhu
D
D
Miller-Graziano
C L
CL
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001681:Biological Assay; D002056:Burns / Q000097:blood / Q000276:immunology / Q000503:physiopathology*; D005260:Female; D006801:Humans; D007249:Inflammation; D008297:Male; D051379:Mice; D008875:Middle Aged; D009000:Monocytes / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012016:Reference Values; D012044:Regression Analysis; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis*; D014947:Wounds and Injuries / Q000097:blood / Q000276:immunology / Q000503:physiopathology*
D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha