Furse R K, Kodys K, Zhu D, Miller-Graziano C L
University of Massachusetts Medical Center, Department of Surgery, Worcester 01655, USA.
J Leukoc Biol. 1997 Oct;62(4):524-34. doi: 10.1002/jlb.62.4.524.
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.
创伤后肿瘤坏死因子α（TNF-α）升高似乎在介导全身炎症反应综合征（SIRS）的许多症状中起关键作用，导致晚期死亡。虽然单核细胞（mphi）产生TNF-α增加在这种TNF-α升高中起关键作用，但导致mphi产生TNF-α增加的分子机制尚未阐明。我们证明，虽然所有创伤患者的mphi中TNF-α mRNA水平都升高，且产生的TNF-α蛋白水平也升高，但在大多数患者中，这些升高的TNF-α mRNA水平处于正常转录和转录后控制之下。因此，这些患者的mphi产生TNF-α增加可能是由于创伤释放的介质对这些mphi的预激活。然而，一小部分患者（死亡率为57%）主要产生膜相关型TNF-α。这些患者的mphi在体外刺激下TNF-α mRNA积累显著增加。所有这些患者都经历了SIRS。在这部分患者的mphi中，TNF-α mRNA稳定性异常增加。TNF-α mRNA稳定性的这种增加可能导致TNF-α蛋白产生毁灭性的延长。创伤后mphi中TNF-α mRNA稳定性增加的这一证明代表了膜相关TNF-α蛋白升高、死亡率增加以及这种情况发生机制之间的一种新关联。
