Prostaglandin E2-synthesizing enzymes in fever:: differential transcriptional regulation
Prostaglandin E2-synthesizing enzymes in fever:: differential transcriptional regulation
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DOI：
10.1152/ajpregu.00347.2002
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发表时间：
2002-11-01
影响因子：
2.8
通讯作者：
Romanovsky, AA
中科院分区：
文献类型：
--
作者：
Ivanov, AI;Pero, RS;Romanovsky, AA
脂多糖（LPS）的发热反应包括三个阶段（I-III期），所有阶段都需要重新合成前列腺素（PG） E-2。激活PGE(2)-合成酶的主要机制是转录上调。研究了Wistar-Kyoto大鼠静脉注射LPS （50 mug/kg）后的三期发热反应。采用实时RT-PCR技术，定量测定7种PGE(2)-合成酶在lps加工器官（肝、肺）和脑“发热中枢”（下丘脑）中的表达。第一阶段涉及肝脏和肺部功能偶联环氧化酶(COX)-2和微粒体PGE合成酶（PGES）的转录上调。II期包括外周和大脑中主要炎症通路中所有酶的显著上调，即分泌磷脂酶（PL） A(2)- iia -> COX- 2 -> mPGES。在第三阶段，下丘脑细胞浆(c) PLA(2)- α被诱导，下丘脑和肝脏sPLA(2)- iia和mPGES进一步上调，所研究的所有组织中COX- 1和COX- 2的表达下降。LPS均未诱导sPLA(2)-V和cPGES。mPGES和sPLA(2)-IIA的高水平上调（分别为1257倍和133倍）使这些酶成为抗炎治疗的有吸引力的靶点。
The febrile response to lipopolysaccharide (LPS) consists of three phases (phases I-III), all requiring de novo synthesis of prostaglandin (PG) E-2. The major mechanism for activation of PGE(2)-synthesizing enzymes is transcriptional upregulation. The triphasic febrile response of Wistar-Kyoto rats to intravenous LPS (50 mug/kg) was studied. Using real-time RT-PCR, the expression of seven PGE(2)-synthesizing enzymes in the LPS-processing organs (liver and lungs) and the brain "febrigenic center" (hypothalamus) was quantified. Phase I involved transcriptional upregulation of the functionally coupled cyclooxygenase (COX)-2 and microsomal (m) PGE synthase (PGES) in the liver and lungs. Phase II entailed robust upregulation of all enzymes of the major inflammatory pathway, i.e., secretory (s) phospholipase (PL) A(2)-IIA --> COX- 2 --> mPGES, in both the periphery and brain. Phase III was accompanied by the induction of cytosolic (c) PLA(2)-alpha in the hypothalamus, further upregulation of sPLA(2)-IIA and mPGES in the hypothalamus and liver, and a decrease in the expression of COX- 1 and COX- 2 in all tissues studied. Neither sPLA(2)-V nor cPGES was induced by LPS. The high magnitude of upregulation of mPGES and sPLA(2)-IIA (1,257-fold and 133-fold, respectively) makes these enzymes attractive targets for anti-inflammatory therapy.