Molecular basis of endotoxin tolerance
Molecular basis of endotoxin tolerance
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DOI：
10.1111/j.1749-6632.1998.tb09020.x
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发表时间：
1998-01-01
期刊：
影响因子：
--
通讯作者：
Cook, JA
中科院分区：
文献类型：
--
作者：
Cook, JA
Septic shock is often associated with the release of bacterial lipopolysaccharide (LPS) from the cell wall of gram-negative bacteria. LPS-stimulated release of macrophage (M∅) mediators produces a systemic inflammatory response responsible for the high mortality in sepsis. 1, 2 Despite the highly lethal nature of LPS, preexposure to sublethal doses of LPS induces an acquired state of resistance to subsequent challenge with lethal doses of LPS. 3, 4 This phenomenon is referred to as LPS tolerance and is largely characterized by reduced M∅ inflammatory mediator production. M∅ mediator production under these conditions is not globally suppressed but appears to be differentially altered or reprogrammed. Whereas tumor necrosis factor (TNFα) and arachidonic acid metabolites are decreased, 5 other mediators, for example, nitric oxide, IL-6, 5, 6 and IL-10, 7 remain unchanged or even increase. Indeed, upregulation of nitric oxide production6 and IL-107 have been proposed as partial mechanisms of tolerance. Tolerance could be mediated at the level of receptor binding or signal transduction—events that modify gene induction, transcription, or protein translation. Although multiple receptors bind LPS, 8 changes in receptor binding do not appear to play a role in tolerance. 9, 10 Gene transcription of TNFα and IL-1β is decreased in tolerance. 9–11 The transcription factor NFK-β is activated by LPS and translocation to the nucleus where transcription is induced. One hypothesis is that over expression of an inactive form of NFK-β composed of P50 homodimers suppresses DNA binding and thus transcription. 12 Other investigators have implicated repressor proteins in LPS tolerance that block transcription signaling. 13, 14 Other important modulators of LPS signaling include tyrosine kinase and protein kinase C. However, no clear role for them in tolerance has been established. Inhibitors of tyrosine kinases do not block the abilities of LPS or induced tolerance in mouse peritoneal M∅. 15 LPS tolerance also is not mediated by direct down-regulation of protein kinase C. 16, 17Guanine nucleotide regulatory (G) proteins are proteins that bind GTP and have intrinsic GTPase activity. The heterotrimeric G proteins are membrane-bound and couple receptors to second messenger systems. The importance of these proteins in LPS-stimulated signal transduction has been demonstrated by studies with pertussis toxin (PT), which prevents receptor coupling with Gi proteins by ADP-ribosylating and inactivating them. PT pretreatment in vitro blocks LPS-stimulated, IL-1 mRNA transcription in U937 cells, 18 PGE2 production in rat mesangial cells, 19 T× B2 and 6-keto-PGF1α production in rat peritoneal macrophages, 20 PLD stimulation in rat mesangial and THP-1 cells, 21 and T× B2 production in THP-1 cells. 22 Because LPS-stimulated AA metabolism is mediated by Giα proteins, studies were initiated to determine whether Giα and/or other G proteins are reduced in function and content in LPS tolerance. Rats were rendered tolerant by sublethal doses of Salmonella enteritidis LPS or sublethal administration of human recombi-
