Resistin对炎症信号途径的调控研究
摘要
Resistin称抗素(也称FIZZ3),是一种含有114个氨基酸的细胞因子。近来发现resistin具有一系列前炎症因子的特征,在炎症中能够诱导血管内皮细胞粘附分子的表达,从而导致白细胞向各个炎症组织中的浸润。尽管resistin在炎症发生中已有不少报道,但其与经典炎症信号途径的关系,在炎症中的作用及其调控机制尚未阐明。
环氧合酶2(COX-2)是前列腺素合成中的一个限速酶。在人体中存在两种不同的COX异构体,分别称为COX-1和COX-2。其中COX-2是一种经过诱导而产生的酶,在正常生理条件下维持较低的表达水平,但在炎症部位表达上调,催化炎性PGs的合成并诱发炎症反应。此外,COX-2的启动子上存在NF-κB的结合元件,可受转录因子NF-κB调控。一些重要的炎症因子例如TNFa和IL-1可通过激活NF-κB而上调COX-2的表达。
本研究以resistin为研究对象,采用real-time PCR、Western Blotting和细胞转染等技术,系统研究了resistin通过经典的炎症信号途径上调COX-2的基因表达及抗炎肽C15对resistin等引起的炎症反应的抑制作用分子机制,结果如下：
1.在巨噬细胞内分别转染猪和小鼠resistin的超表达载体,采用real-timePCR和Western Blotting方法检测细胞内源的COX-2的mRNA和蛋白质水平的表达变化。结果表明,resistin在RAW264.7巨噬细胞系中可以显著地上调COX-2的mRNA和蛋白质的表达。更重要的是,通过原核表达制备了抗resistin的抗体,用抗体处理可以抵消resistin的这种作用。
2.以巨噬细胞为模型,通过负显性IκBα突变体和PDTC这两种抑制物质研究了resistin对COX-2的信号转导途径的调控。结果表明,无论是超表达负显性IκBα突变体载体,还是用抑制剂PDTC刺激,都可以抑制resistin对COX-2的诱导作用。进一步的研究证实,resistin的超表达可以上调NF-κB分子中的p65亚基的表达,进而诱导COX-2的表达水平的上升。
3.以resistin对小鼠巨噬细胞作不同时间梯度的处理,用Western Blotting方法分析resistin对一种MAPKKK激酶TAK1 (Transforming growth factorβactivated kinase 1)的磷酸化程度的影响。结果表明,resistin可以显著上调TAK1的磷酸化水平。
4.以促炎物质resistin,LPS,PA分别和C15共同处理小鼠巨噬细胞,检测炎症基因COX-2和iNOS (inducible nitric oxide synthase)的表达变化。结果表明,炎症基因COX-2和iNOS可以被三种促炎物质诱导表达,并且这种诱导的情况可以显著被C15所抑制住。
5.在巨噬细胞中,以LPS在不同时间梯度刺激细胞,用细胞免疫荧光的方法检测NF-κB的p65亚基的入核情况。结果证实,C15可以明显抑制LPS所导致的p65的入核情况,表明C15是通过阻止NF-κB的p65亚基入核,从而抑制相关炎症因子的表达,进而表现出一定的抗炎活性。
Resistin is a 114-amino-acid polypeptide which belongs to resistin-like molecule (RELM) family characterized by a highly conserved cysteine-rich C terminus. Recently, resistin has emerged as a novel pro-inflammatory factor. The association between resistin and inflammation has also been demonstrated in rheumatoid arthritis and other diseases, where resistin is capable of inducing vascular adhesion molecule expression and promoting leukocyte infiltration into tissues.
Two cyclooxygenease, COX-1 and COX-2, have been identified as the key enzymes regulating the production of prostaglandins. COX-2 is an inflammation-induced enzyme that remains undetectable in most mammalian tissues under basal conditions and is highly activated at the sites of inflammation. Some important pro-inflammatory cytokines, such as TNF-alpha, can also upregulate COX-2 expression via NF-kappa B pathway.
In this study, by choosing the important cytokine resistin and using real-time PCR, transfection and western blotting, we studied the regulation effect of COX-2 by resistin, and also researched the anti-inflammatory effect of chemerin-15 and got the following results:
1. Compared with controls, resistin remarkably upregulated COX-2 expression in RAW264.7 macrophage cells. Administration of anti-resistin antibody could reverse this effect.
2. Induction of COX-2 by resistin was markedly reduced in the presence of either dominant negative mutant IκBαor PDTC, a pharmacological inhibitor of NF-κB. NF-κB subunit p65 was also upregulated by resistin.
3. Moreover, we found that transforming growth factor-β-activated kinase 1 (TAK1), a mitogen-activated protein kinase kinase kinase (MAPKKK), could be activated in response to resistin.
4. Stimulated RAW cells with LPS, resistin and C15, measured the expression of COX-2 and iNOS. The results indicated that the inducing of COX-2 and iNOS could markedly reduced by C15.
5. We used macrophages as a model, using LPS as a proinflammatory substance representation measured the translocation of NF-κB subunit p65. The results indicated that the ranslocation of p65 induced by LPS could be obviously inhibited by C15. This result also proved the pecific mechanism of C15 generating antiinflammation.
环氧合酶2(COX-2)是前列腺素合成中的一个限速酶。在人体中存在两种不同的COX异构体,分别称为COX-1和COX-2。其中COX-2是一种经过诱导而产生的酶,在正常生理条件下维持较低的表达水平,但在炎症部位表达上调,催化炎性PGs的合成并诱发炎症反应。此外,COX-2的启动子上存在NF-κB的结合元件,可受转录因子NF-κB调控。一些重要的炎症因子例如TNFa和IL-1可通过激活NF-κB而上调COX-2的表达。
本研究以resistin为研究对象,采用real-time PCR、Western Blotting和细胞转染等技术,系统研究了resistin通过经典的炎症信号途径上调COX-2的基因表达及抗炎肽C15对resistin等引起的炎症反应的抑制作用分子机制,结果如下：
1.在巨噬细胞内分别转染猪和小鼠resistin的超表达载体,采用real-timePCR和Western Blotting方法检测细胞内源的COX-2的mRNA和蛋白质水平的表达变化。结果表明,resistin在RAW264.7巨噬细胞系中可以显著地上调COX-2的mRNA和蛋白质的表达。更重要的是,通过原核表达制备了抗resistin的抗体,用抗体处理可以抵消resistin的这种作用。
2.以巨噬细胞为模型,通过负显性IκBα突变体和PDTC这两种抑制物质研究了resistin对COX-2的信号转导途径的调控。结果表明,无论是超表达负显性IκBα突变体载体,还是用抑制剂PDTC刺激,都可以抑制resistin对COX-2的诱导作用。进一步的研究证实,resistin的超表达可以上调NF-κB分子中的p65亚基的表达,进而诱导COX-2的表达水平的上升。
3.以resistin对小鼠巨噬细胞作不同时间梯度的处理,用Western Blotting方法分析resistin对一种MAPKKK激酶TAK1 (Transforming growth factorβactivated kinase 1)的磷酸化程度的影响。结果表明,resistin可以显著上调TAK1的磷酸化水平。
4.以促炎物质resistin,LPS,PA分别和C15共同处理小鼠巨噬细胞,检测炎症基因COX-2和iNOS (inducible nitric oxide synthase)的表达变化。结果表明,炎症基因COX-2和iNOS可以被三种促炎物质诱导表达,并且这种诱导的情况可以显著被C15所抑制住。
5.在巨噬细胞中,以LPS在不同时间梯度刺激细胞,用细胞免疫荧光的方法检测NF-κB的p65亚基的入核情况。结果证实,C15可以明显抑制LPS所导致的p65的入核情况,表明C15是通过阻止NF-κB的p65亚基入核,从而抑制相关炎症因子的表达,进而表现出一定的抗炎活性。
Resistin is a 114-amino-acid polypeptide which belongs to resistin-like molecule (RELM) family characterized by a highly conserved cysteine-rich C terminus. Recently, resistin has emerged as a novel pro-inflammatory factor. The association between resistin and inflammation has also been demonstrated in rheumatoid arthritis and other diseases, where resistin is capable of inducing vascular adhesion molecule expression and promoting leukocyte infiltration into tissues.
Two cyclooxygenease, COX-1 and COX-2, have been identified as the key enzymes regulating the production of prostaglandins. COX-2 is an inflammation-induced enzyme that remains undetectable in most mammalian tissues under basal conditions and is highly activated at the sites of inflammation. Some important pro-inflammatory cytokines, such as TNF-alpha, can also upregulate COX-2 expression via NF-kappa B pathway.
In this study, by choosing the important cytokine resistin and using real-time PCR, transfection and western blotting, we studied the regulation effect of COX-2 by resistin, and also researched the anti-inflammatory effect of chemerin-15 and got the following results:
1. Compared with controls, resistin remarkably upregulated COX-2 expression in RAW264.7 macrophage cells. Administration of anti-resistin antibody could reverse this effect.
2. Induction of COX-2 by resistin was markedly reduced in the presence of either dominant negative mutant IκBαor PDTC, a pharmacological inhibitor of NF-κB. NF-κB subunit p65 was also upregulated by resistin.
3. Moreover, we found that transforming growth factor-β-activated kinase 1 (TAK1), a mitogen-activated protein kinase kinase kinase (MAPKKK), could be activated in response to resistin.
4. Stimulated RAW cells with LPS, resistin and C15, measured the expression of COX-2 and iNOS. The results indicated that the inducing of COX-2 and iNOS could markedly reduced by C15.
5. We used macrophages as a model, using LPS as a proinflammatory substance representation measured the translocation of NF-κB subunit p65. The results indicated that the ranslocation of p65 induced by LPS could be obviously inhibited by C15. This result also proved the pecific mechanism of C15 generating antiinflammation.
引文
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