Interferon regulatory factor (IRF)-1 and IRF-2 regulate interferon gamma-dependent cyclooxygenase 2 expression.
Interferon regulatory factor (IRF)-1 and IRF-2 regulate interferon gamma-dependent cyclooxygenase 2 expression.
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DOI：
10.1084/jem.191.12.2131
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发表时间：
2000-06-19
期刊：
影响因子：
--
通讯作者：
Vogel SN
中科院分区：
文献类型：
--
作者：
Blanco JC;Contursi C;Salkowski CA;DeWitt DL;Ozato K;Vogel SN
环氧合酶（考克斯）是起始花生四烯酸转化为前列腺素类的限速酶。考克斯-2是可诱导的同种型，其被促炎剂上调，引发许多前列腺素类介导的炎症病理学方面。在本研究中，我们证明干扰素（IFN）-γ单独或与脂多糖（LPS）或白细胞介素1α（IL 1α）协同诱导小鼠腹腔巨噬细胞考克斯-2的表达，这通过考克斯-2蛋白水平和前列腺素E2（PGE 2）释放的变化来证实。在缺乏IFN调节因子（IRF）-1的巨噬细胞中，考克斯-2的诱导被消除，这与注射LPS的IRF-1−/−小鼠中减弱的肝脏mRNA反应一致。相反，巨噬细胞中IRF-2的缺失导致基础和诱导型考克斯-2基因和蛋白表达以及IFN-γ刺激的PGE 2释放显著增加，鉴定IRF-2为该启动子的负调节因子。在小鼠考克斯-2启动子中鉴定了两个IFN刺激应答元件，它们在人考克斯-2基因中高度保守。两者均结合内源性IRF-1和IRF-2，并以IRF-1/2依赖性方式调节转录。我们的数据最终证明了IFN-γ作为考克斯-2基因的直接激活剂和共激活剂的重要性，以及IRF-1/2家族成员在此过程中的核心作用。
Cyclooxygenases (Cox) are rate-limiting enzymes that initiate the conversion of arachidonic acid to prostanoids. Cox-2 is the inducible isoform that is upregulated by proinflammatory agents, initiating many prostanoid-mediated pathological aspects of inflammation. In this study, we demonstrate that interferon (IFN)-γ alone or in synergy with lipopolysaccharide (LPS) or interleukin 1α induces Cox-2 expression in mouse peritoneal macrophages, which is paralleled by changes in Cox-2 protein levels and prostaglandin E2 (PGE2) release. Induction of Cox-2 was abrogated in macrophages that lack IFN regulatory factor (IRF)-1, consistent with an attenuated hepatic mRNA response in IRF-1−/− mice injected with LPS. Conversely, the absence of IRF-2 in macrophages resulted in a significant increase in both basal and inducible Cox-2 gene and protein expression as well as IFN-γ–stimulated PGE2 release, identifying IRF-2 as negative regulator of this promoter. Two IFN stimulation response elements were identified in the mouse Cox-2 promoter that were highly conserved in the human Cox-2 gene. Both bind endogenous IRF-1 and IRF-2 and regulate transcription in an IRF-1/2–dependent manner. Our data demonstrate conclusively the importance of IFN-γ as a direct activator and coactivator of the Cox-2 gene, and the central role of IRF-1/2 family members in this process.
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影响因子：
15.9
作者：
Asano, K;Nakamura, H;Drazen, JM
通讯作者：
Drazen, JM
影响因子：
4.8
作者：
Coccia, EM;Passini, N;Rogge, L
通讯作者：
Rogge, L
影响因子：
3.1
作者：
BARBER, SA;FULTZ, MJ;VOGEL, SN
通讯作者：
VOGEL, SN
DOI：
10.1073/pnas.97.1.91
发表时间：
2000-01-04
影响因子：
11.1
作者：
Contursi, C;Wang, IM;Ozato, K
通讯作者：
Ozato, K
DOI：
10.1006/bbrc.1998.8222
发表时间：
1998-03-06
影响因子：
3.1
作者：
Inoue, H;Tanabe, T
通讯作者：
Tanabe, T