Estrogen regulates transcription factors STAT-1 and NF-kappaB to promote inducible nitric oxide synthase and inflammatory responses.
Estrogen regulates transcription factors STAT-1 and NF-kappaB to promote inducible nitric oxide synthase and inflammatory responses.
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DOI：
10.4049/jimmunol.0901737
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发表时间：
2009-12-01
期刊：
影响因子：
--
通讯作者：
Ahmed SA
中科院分区：
文献类型：
--
作者：
Dai R;Phillips RA;Karpuzoglu E;Khan D;Ahmed SA
Estrogen regulation of inflammatory responses has broad physiological and pathological consequences. However, the molecular mechanism of estrogen regulation of inflammation is still poorly understood. In the present study, we report that activation of both IFNγ-STAT-1 and NF-κB signaling is essential for Con A-induced iNOS/nitric oxide in murine splenocytes. Interestingly, estrogen enhances STAT-1 DNA binding activity without increasing the expression of phosphorylated and total STAT-1 protein. We have reported that estrogen blocks the nuclear expression of NF-κB p65 and modifies nuclear NF-κBp50. Here, we demonstrated that both nuclear STAT-1 and NF-κB are modified by serine protease mediated proteolysis, which resulted in altered STAT-1 and NF-κB activity/signaling in splenocytes from estrogen-treated mice. Selected inhibition of serine protease activity with AEBSF (4-(2-Aminoethyl) benzenesulfonyl fluoride hydrochloride) restores the nuclear expression of full-length STAT-1 and NF-κB proteins, which causes decreased STAT-1 DNA binding activity and formation of NF-κB p65/p50 binding complexes in nuclei of splenocytes from estrogen-treated mice. Consequently, there is significantly decreased iNOS and IFNγ production in AEBSF treated splenocytes from estrogen-treated mice, which suggests a positive regulatory role of truncated STAT-1 and/or NF-κB. Interestingly, there is increased production of MCP-1 in STAT-1 or NF-κB siRNA transfected cells, as well as in AEBSF treated splenocytes from estrogen-treated mice. These data suggest a differential role of truncated STAT-1 and NF-κB in regulation of various inflammatory molecules in splenocytes from estrogen-treated mice. Together, our data reveal a novel molecular mechanism of estrogen-mediated promotion of inflammatory responses, which involves post-translational modification of STAT-1 and NF-κB proteins.
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