瘢痕疙瘩自身免疫疾病特征和多聚嘧啶序列结合蛋白为治疗靶点的研究
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摘要
研究背景：
瘢痕疙瘩发病机制尚不清楚,并缺乏切实有效的治疗措施,一直是临床治疗难题。由各种原因导致的炎症反应在诱发瘢痕疙瘩、及其逐渐发展为以细胞外基质过度堆积为特点的纤维化疾病过程中有重要作用,这与很多自身免疫疾病非常类似。自身免疫疾病也是通过启动炎性反应导致组织损伤,长期炎症反应最终导致组织纤维化,例如硬皮病导致的皮肤纤维化。所以我们推测瘢痕疙瘩可能具有自身免疫疾病的相关特征。此外,瘢痕疙瘩具有细胞增殖旺盛和持续浸润生长等肿瘤特征。多聚嘧啶序列结合蛋白(PTB)是广泛表达于多种细胞细胞核的RNA结合蛋白,近年来研究发现PTB在多种肿瘤中的表达升高,并具有促进肿瘤细胞增殖和浸润转移的作用,被认为是肿瘤治疗的潜在靶点。而PTB在瘢痕疙瘩中的表达以及能否作为治疗靶点尚未见报道。
研究目的：
1.明确瘢痕疙瘩是否具有自身免疫疾病的相关病理特征,并筛查可能作为实验室诊断指标的自身抗体。
2.明确PTB在瘢痕疙瘩中的表达及功能,并探讨PTB作为瘢痕疙瘩治疗靶点的可能性。
研究方法和结果：
1.瘢痕疙瘩患者自身免疫疾病相关特征的研究
方法：首先采用间接免疫荧光和线性免疫分析,对28例瘢痕疙瘩患者和28例健康者的血清,进行了常规抗核抗体谱的筛查。同时通过ELISA方法检测血清中抗-hnRNPA2B1(抗—核不均一性核糖核蛋白A2B1)自身抗体滴度和hnRNPA2B1蛋白浓度。另外,采用Western bloting的方法检测了hnRNPA2B1蛋白在瘢痕疙瘩和正常皮肤组织中的表达。最后采用直接免疫荧光和免疫组织化学的方法,分别对瘢痕疙瘩组织内免疫复合物的沉积和免疫细胞浸润情况进行了观察。
结果：在瘢痕疙瘩患者和健康者中,仅个别血清表现出抗核抗体或者特异性抗核抗体阳性,无统计学意义。瘢痕疙瘩患者血清中抗-hnRNPA2B1滴度显著高于健康者,两组血清中hnRNPA2B1蛋白浓度并无差异。瘢痕疙瘩组织内hnRNPA2B1蛋白含量明显高于正常皮肤。在瘢痕疙瘩组织内可见IgA、IgM、C3和C1q沉积,但正常皮肤内未见免疫复合物的沉积。同时瘢痕疙瘩组织内朗格汉斯细胞、B淋巴细胞、巨噬细胞、T淋巴细胞数量均明显高于正常皮肤。
2.多聚嘧啶序列结合蛋白(PTB)作为瘢痕疙瘩治疗靶点的研究
2.1PTB在瘢痕疙瘩组织和细胞中的表达及功能
方法：首先采用HE染色和天狼星红染色比较了瘢痕疙瘩和正常皮肤组织学和胶原纤维构成的差异；通过Ki-67和增殖细胞核抗原(PCNA)免疫组化染色对组织内细胞增殖进行了评价,并对PTB也进行了免疫组化染色；采用Real time PCR的方法,对PTB和细胞外基质相关基因的表达进行了检测。另外在体外培养了瘢痕疙瘩和正常皮肤成纤维细胞,检测了两种成纤维细胞的PTB和细胞外基质表达。并用RNA干扰技术对瘢痕疙瘩成纤维细胞的PTB进行了敲减,敲减之后分别用Brdu标记和Real time PCR的方法检测了细胞增殖和细胞外基质表达的改变,并对增殖相关基因的选择性剪切进行了研究。
结果：组织学观察发现瘢痕疙瘩组织内有大量细胞外基质的堆积,细胞密度明显增加,并且从浅层至深层III型胶原纤维相对含量逐渐下降而I型胶原纤维相对含量逐渐升高。瘢痕疙瘩组织内Ki-67和PCNA阳性细胞显著增多,编码细胞外基质的基因COL1A1、COL3A1和FN1表达增加,同时伴随PTB表达升高。体外培养的瘢痕疙瘩成纤维细胞COL1A1和COL3A1表达与正常皮肤成纤维细胞无明显差异,但PTB的表达仍然高于正常皮肤成纤维细胞。采用siRNA(小干扰RNA)将PTB进行敲减后,瘢痕疙瘩成纤维细胞增殖受到抑制,但细胞外基质相关基因的表达未见显著变化；进一步研究发现PTB敲减使三个增殖相关基因(PKM、USP5、RNT4)的选择性剪切均发生了相应改变。
2.2PTB对TGF-β1(转化生长因子-β1)促进细胞外基质分泌作用的影响
方法：采用含不同浓度TGF-β1(Ong/ml、5ng/ml、10ng/ml、20ng/ml)的培养基培养成纤维细胞；分别在培养后0、2、6、12、24、48h,对成纤维细胞的PTB和细胞外基质表达进行了检测。同时在TGF-β1培养条件下对PTB进行敲减,敲减后检测细胞外基质分泌情况。
结果：TGF-β1处理12h后瘢痕疙瘩成纤维细胞的COL1A1、FN1、ACTA2和PTB表达开始升高,并有一定的浓度依赖性；TGF-β1也可以促进正常皮肤成纤维细胞表达上述基因,但升高时间较瘢痕疙瘩成纤维细胞中延迟并升高幅度较低。在TGF-β1培养条件下,对PTB进行敲减可以抑制瘢痕疙瘩成纤维细胞FN1的表达。
2.3PTB敲减对裸鼠体内瘢痕疙瘩移植物的作用
方法：为明确PTB是否可以作为瘢痕疙瘩治疗靶点,我们通过将瘢痕疙瘩组织块移植至裸鼠皮下的方法,建立了瘢痕疙瘩动物模型。每周向移植物内注射2次PTBsiRNA或对照siRNA,共注射4周。4周后取材,对移植物称重,进行组织学染色,以及相关基因表达的检测。
结果：称重发现实验组移植物重量小于对照组；组织学染色显示实验组细胞密度和Ⅲ型胶原纤维含量降低；Real time PCR结果显示实验组PTB的表达水平低于对照组,同时伴随COL3A1和FN1表达降低。
研究结论：
1.在瘢痕疙瘩患者血清中首次检测到抗-hnRNPA2Bl自身抗体,瘢痕疙瘩组织中有免疫复合物的沉积,以及以CD20+B淋巴细胞为主的大量免疫细胞浸润,这些均提示瘢痕疙瘩具有自身免疫疾病的相关病理特征。
2.PTB在瘢痕疙瘩组织和成纤维细胞内表达增高。将PTB敲减后,在普通培养条件下可以改变增殖相关基因的选择性剪切并抑制成纤维细胞增殖,在TGF-β1培养条件下可以抑制FN1表达；在裸鼠体内瘢痕疙瘩移植物中敲减PTB后,移植物显著萎缩,并伴随COL3A1和FN1表达的降低。这些研究结果表明PTB可能通过调控细胞增殖和细胞外基质表达,参与了瘢痕疙瘩形成,并可以作为瘢痕疙瘩治疗靶点。
Background:
The pathogenesis of keloid remains unclear, its high recurrence rate despite a variety of treatments makes keloid one of the major unsolved clinical challenges in wound healing. The pathology of keloid is characterized by excessive extracellular matrix deposition and a great number of infiltrated immune cells, so keloid could been regarded as a fibrotic skin disease. Meanwhile, in autoimmune diseases, triggering of the inflammation response can lead to tissue injury and subsequent organ fibrosis. When the skin is involved in autoimmune disease, skin fibrosis such as that seen in scleroderma can occur. In this study, we propose that keloids possess features of autoimmune disease and verified this hypothesis.
Keloids behave like tumors as they grow beyond the boundaries of the original wound margin, invade the surrounding normal tissue, do not regress spontaneously, have a rich vascular supply and recur despite treatments. Polypyrimidine tract binding protein(PTB) is a57-kDa RNA binding protein and express in nucleus of various cells. Recently, a great number of studies have found PTB increased in a few of tumors and PTB can promote tumor cells proliferation and metastasis. Therefore, PTB was regarded as a therapeutic target for tumor. We think PTB is also a therapeutic target for keloid.
Objectives:
1. To verify whether keloid is a fibrotic disease mediated by autoimmune response, and attempt to find a laboratory indication for the diagnosis of keloid.
2. To explore the role of PTB in keloid and confirm whether PTB be a potential molecular therapeutic target for keloid.
Methods and Results:
1. Study on keloid patients have some features of autoimmune disease
Methods:Routine anti-nuclear antibody profile was detected in sera from28keloid patients and28healthy controls, using indirect immunofluorescence and line immunoassay. The anti-hnRNPA2B1autoantibody and hnRNPA2B1protein concentration in sera were evaluated by ELISA, while western bloting was used to examine hnRNPA2B1protein expression in keloid and normal tissues. Immune complex deposits in keloid and normal skin were evaluated by direct immunofluorescence. Lastly, immune cell infiltration in keloid tissue was detected with immunohistochemical staining.
Results:A very small number of patients or healthy controls were positive for ANA or a specific ANA, which did not reach statistical significance. Anti-hnRNPA2Bl levels in sera from keloid patients and hnRNPA2B1protein in keloid tissues were elevated, while IgA, IgM, C3and Clq deposits were found in keloid tissues but not normal skin. The number of Langerhans cells, macrophages, B lymphocytes and T lymphocytes were increased in keloids compared to normal skin.
2. Study on polypyrimidine tract binding protein(PTB) as a therapeutic target for keloid
2.1The expression and function of PTB in keloid tissue and fibroblast
Methods:The histology of keloid and normal skin was observed using HE staining and sirius red staining. Immunohistochemistry for Ki-67and PCNA was performed to determine cell proliferation, while immunohistochemistry for PTB was also done. The mRNA of PTB and some genes coding extracellular matrix was detected by real time PCR. Fibroblasts isolated from keloid and normal skin were cultured in normal culture condition and PTB expression as well as extracellular matrix synthesis were valuated. PTB was knockdown using siRNA, cell proliferation and extracelluar matrix synthesis were determined following PTB knockdown.
Results:Histologically, there were excessive extracellular matrix and infiltrated cells in keloid and different tissue layers presented different histological features. In keloid tissue, the number of Ki-67and PCNA positive cells was increased and the expression of COL1A1, COL3A1and FN1was upregulated, which were accompanied by PTB increasing. In fibroblasts from keloid tissues, the expression of PTB, FN1and ACTA2were upregulated, but not COL1A1and COL3A1. In normal culture condition, PTB knockdown suppressed cell proliferation and changed the alternative splicing of some gene related to cell proliferation, however, extracellular matrix expression was not influenced.
2.2The influence of PTB on TGF-β1promoting the expression of genes coding extracellular matrix
Methods:To simulate keloid microenvironment, fibroblasts were cultured in medium containing a different concentration of TGF-β1(Ong/ml,5ng/ml,10ng/ml,20ng/ml). At0,2,6,12,24,48h following TGF-β1treatment, the expression of PTB and extracellular matrix was determined. In the condition of TGF-β1, PTB was also knockdown and extracellular matrix was detected following PTB knockdown.
Results:In fibroblasts from keloid tissues, TGF-β1promoted PTB, COL1A1, FN1and ACTA2expression, as well as the function of TGF-β1was concentration and time dependent. In fibroblasts from normal skin, TGF-β1promoted PTB, COL1A1, FN1and ACTA2expression, however which was not obvious as that in fibroblasts from keloid tissues. In TGF-β1culture condition, PTB knockdown suppressed FN1expression.
2.3The influence of PTB knockdown on transplanted keloid
Methods:To confirm whether PTB is a potential therapeutic target for keloid, we transplanted keloid tissues into nude mice to establish an animal model for keloid. PTB siRNA and control siRNA were injected into transplants, twice a week, for four weeks. After four weeks, transplants were harvested and weighed. The histology of transplants was observed, while PTB and extracelluar matrix expression were valuated.
Results:The weight of transplants from PTB siRNA group was less than control siRNA group. Histologically, there was less cells and III type collagen fibres in transplants from PTB siRNA group. Real time PCR results show PTB, COL3A1and FN1expression were downregulated in PTB siRNA group.
Conclusion:
1. The anti-hnRNPA2Bl titer was firstly found elevated in sera from keloid patients, with immune complex deposits and CD20+B lymphocyte based on immune cell infiltration detected in keloid tissues. These findings suggest that keloid is a fibrotic skin disease mediated by autoimmune responses.
2. PTB increased in tissues and fibroblasts from keloid. PTB knockdown suppressed fibroblasts proliferation in normal culture condition and downregulated FN1expression in TGF-β1culture condition. In keloid transplanted nude mice model, PTB knockdown suppressed COL3A1and FN1expression and accelerated transplants regression. These results suggest PTB may involve in keloid development and been a potential therapeutic target for keloids.
瘢痕疙瘩发病机制尚不清楚,并缺乏切实有效的治疗措施,一直是临床治疗难题。由各种原因导致的炎症反应在诱发瘢痕疙瘩、及其逐渐发展为以细胞外基质过度堆积为特点的纤维化疾病过程中有重要作用,这与很多自身免疫疾病非常类似。自身免疫疾病也是通过启动炎性反应导致组织损伤,长期炎症反应最终导致组织纤维化,例如硬皮病导致的皮肤纤维化。所以我们推测瘢痕疙瘩可能具有自身免疫疾病的相关特征。此外,瘢痕疙瘩具有细胞增殖旺盛和持续浸润生长等肿瘤特征。多聚嘧啶序列结合蛋白(PTB)是广泛表达于多种细胞细胞核的RNA结合蛋白,近年来研究发现PTB在多种肿瘤中的表达升高,并具有促进肿瘤细胞增殖和浸润转移的作用,被认为是肿瘤治疗的潜在靶点。而PTB在瘢痕疙瘩中的表达以及能否作为治疗靶点尚未见报道。
研究目的：
1.明确瘢痕疙瘩是否具有自身免疫疾病的相关病理特征,并筛查可能作为实验室诊断指标的自身抗体。
2.明确PTB在瘢痕疙瘩中的表达及功能,并探讨PTB作为瘢痕疙瘩治疗靶点的可能性。
研究方法和结果：
1.瘢痕疙瘩患者自身免疫疾病相关特征的研究
方法：首先采用间接免疫荧光和线性免疫分析,对28例瘢痕疙瘩患者和28例健康者的血清,进行了常规抗核抗体谱的筛查。同时通过ELISA方法检测血清中抗-hnRNPA2B1(抗—核不均一性核糖核蛋白A2B1)自身抗体滴度和hnRNPA2B1蛋白浓度。另外,采用Western bloting的方法检测了hnRNPA2B1蛋白在瘢痕疙瘩和正常皮肤组织中的表达。最后采用直接免疫荧光和免疫组织化学的方法,分别对瘢痕疙瘩组织内免疫复合物的沉积和免疫细胞浸润情况进行了观察。
结果：在瘢痕疙瘩患者和健康者中,仅个别血清表现出抗核抗体或者特异性抗核抗体阳性,无统计学意义。瘢痕疙瘩患者血清中抗-hnRNPA2B1滴度显著高于健康者,两组血清中hnRNPA2B1蛋白浓度并无差异。瘢痕疙瘩组织内hnRNPA2B1蛋白含量明显高于正常皮肤。在瘢痕疙瘩组织内可见IgA、IgM、C3和C1q沉积,但正常皮肤内未见免疫复合物的沉积。同时瘢痕疙瘩组织内朗格汉斯细胞、B淋巴细胞、巨噬细胞、T淋巴细胞数量均明显高于正常皮肤。
2.多聚嘧啶序列结合蛋白(PTB)作为瘢痕疙瘩治疗靶点的研究
2.1PTB在瘢痕疙瘩组织和细胞中的表达及功能
方法：首先采用HE染色和天狼星红染色比较了瘢痕疙瘩和正常皮肤组织学和胶原纤维构成的差异；通过Ki-67和增殖细胞核抗原(PCNA)免疫组化染色对组织内细胞增殖进行了评价,并对PTB也进行了免疫组化染色；采用Real time PCR的方法,对PTB和细胞外基质相关基因的表达进行了检测。另外在体外培养了瘢痕疙瘩和正常皮肤成纤维细胞,检测了两种成纤维细胞的PTB和细胞外基质表达。并用RNA干扰技术对瘢痕疙瘩成纤维细胞的PTB进行了敲减,敲减之后分别用Brdu标记和Real time PCR的方法检测了细胞增殖和细胞外基质表达的改变,并对增殖相关基因的选择性剪切进行了研究。
结果：组织学观察发现瘢痕疙瘩组织内有大量细胞外基质的堆积,细胞密度明显增加,并且从浅层至深层III型胶原纤维相对含量逐渐下降而I型胶原纤维相对含量逐渐升高。瘢痕疙瘩组织内Ki-67和PCNA阳性细胞显著增多,编码细胞外基质的基因COL1A1、COL3A1和FN1表达增加,同时伴随PTB表达升高。体外培养的瘢痕疙瘩成纤维细胞COL1A1和COL3A1表达与正常皮肤成纤维细胞无明显差异,但PTB的表达仍然高于正常皮肤成纤维细胞。采用siRNA(小干扰RNA)将PTB进行敲减后,瘢痕疙瘩成纤维细胞增殖受到抑制,但细胞外基质相关基因的表达未见显著变化；进一步研究发现PTB敲减使三个增殖相关基因(PKM、USP5、RNT4)的选择性剪切均发生了相应改变。
2.2PTB对TGF-β1(转化生长因子-β1)促进细胞外基质分泌作用的影响
方法：采用含不同浓度TGF-β1(Ong/ml、5ng/ml、10ng/ml、20ng/ml)的培养基培养成纤维细胞；分别在培养后0、2、6、12、24、48h,对成纤维细胞的PTB和细胞外基质表达进行了检测。同时在TGF-β1培养条件下对PTB进行敲减,敲减后检测细胞外基质分泌情况。
结果：TGF-β1处理12h后瘢痕疙瘩成纤维细胞的COL1A1、FN1、ACTA2和PTB表达开始升高,并有一定的浓度依赖性；TGF-β1也可以促进正常皮肤成纤维细胞表达上述基因,但升高时间较瘢痕疙瘩成纤维细胞中延迟并升高幅度较低。在TGF-β1培养条件下,对PTB进行敲减可以抑制瘢痕疙瘩成纤维细胞FN1的表达。
2.3PTB敲减对裸鼠体内瘢痕疙瘩移植物的作用
方法：为明确PTB是否可以作为瘢痕疙瘩治疗靶点,我们通过将瘢痕疙瘩组织块移植至裸鼠皮下的方法,建立了瘢痕疙瘩动物模型。每周向移植物内注射2次PTBsiRNA或对照siRNA,共注射4周。4周后取材,对移植物称重,进行组织学染色,以及相关基因表达的检测。
结果：称重发现实验组移植物重量小于对照组；组织学染色显示实验组细胞密度和Ⅲ型胶原纤维含量降低；Real time PCR结果显示实验组PTB的表达水平低于对照组,同时伴随COL3A1和FN1表达降低。
研究结论：
1.在瘢痕疙瘩患者血清中首次检测到抗-hnRNPA2Bl自身抗体,瘢痕疙瘩组织中有免疫复合物的沉积,以及以CD20+B淋巴细胞为主的大量免疫细胞浸润,这些均提示瘢痕疙瘩具有自身免疫疾病的相关病理特征。
2.PTB在瘢痕疙瘩组织和成纤维细胞内表达增高。将PTB敲减后,在普通培养条件下可以改变增殖相关基因的选择性剪切并抑制成纤维细胞增殖,在TGF-β1培养条件下可以抑制FN1表达；在裸鼠体内瘢痕疙瘩移植物中敲减PTB后,移植物显著萎缩,并伴随COL3A1和FN1表达的降低。这些研究结果表明PTB可能通过调控细胞增殖和细胞外基质表达,参与了瘢痕疙瘩形成,并可以作为瘢痕疙瘩治疗靶点。
Background:
The pathogenesis of keloid remains unclear, its high recurrence rate despite a variety of treatments makes keloid one of the major unsolved clinical challenges in wound healing. The pathology of keloid is characterized by excessive extracellular matrix deposition and a great number of infiltrated immune cells, so keloid could been regarded as a fibrotic skin disease. Meanwhile, in autoimmune diseases, triggering of the inflammation response can lead to tissue injury and subsequent organ fibrosis. When the skin is involved in autoimmune disease, skin fibrosis such as that seen in scleroderma can occur. In this study, we propose that keloids possess features of autoimmune disease and verified this hypothesis.
Keloids behave like tumors as they grow beyond the boundaries of the original wound margin, invade the surrounding normal tissue, do not regress spontaneously, have a rich vascular supply and recur despite treatments. Polypyrimidine tract binding protein(PTB) is a57-kDa RNA binding protein and express in nucleus of various cells. Recently, a great number of studies have found PTB increased in a few of tumors and PTB can promote tumor cells proliferation and metastasis. Therefore, PTB was regarded as a therapeutic target for tumor. We think PTB is also a therapeutic target for keloid.
Objectives:
1. To verify whether keloid is a fibrotic disease mediated by autoimmune response, and attempt to find a laboratory indication for the diagnosis of keloid.
2. To explore the role of PTB in keloid and confirm whether PTB be a potential molecular therapeutic target for keloid.
Methods and Results:
1. Study on keloid patients have some features of autoimmune disease
Methods:Routine anti-nuclear antibody profile was detected in sera from28keloid patients and28healthy controls, using indirect immunofluorescence and line immunoassay. The anti-hnRNPA2B1autoantibody and hnRNPA2B1protein concentration in sera were evaluated by ELISA, while western bloting was used to examine hnRNPA2B1protein expression in keloid and normal tissues. Immune complex deposits in keloid and normal skin were evaluated by direct immunofluorescence. Lastly, immune cell infiltration in keloid tissue was detected with immunohistochemical staining.
Results:A very small number of patients or healthy controls were positive for ANA or a specific ANA, which did not reach statistical significance. Anti-hnRNPA2Bl levels in sera from keloid patients and hnRNPA2B1protein in keloid tissues were elevated, while IgA, IgM, C3and Clq deposits were found in keloid tissues but not normal skin. The number of Langerhans cells, macrophages, B lymphocytes and T lymphocytes were increased in keloids compared to normal skin.
2. Study on polypyrimidine tract binding protein(PTB) as a therapeutic target for keloid
2.1The expression and function of PTB in keloid tissue and fibroblast
Methods:The histology of keloid and normal skin was observed using HE staining and sirius red staining. Immunohistochemistry for Ki-67and PCNA was performed to determine cell proliferation, while immunohistochemistry for PTB was also done. The mRNA of PTB and some genes coding extracellular matrix was detected by real time PCR. Fibroblasts isolated from keloid and normal skin were cultured in normal culture condition and PTB expression as well as extracellular matrix synthesis were valuated. PTB was knockdown using siRNA, cell proliferation and extracelluar matrix synthesis were determined following PTB knockdown.
Results:Histologically, there were excessive extracellular matrix and infiltrated cells in keloid and different tissue layers presented different histological features. In keloid tissue, the number of Ki-67and PCNA positive cells was increased and the expression of COL1A1, COL3A1and FN1was upregulated, which were accompanied by PTB increasing. In fibroblasts from keloid tissues, the expression of PTB, FN1and ACTA2were upregulated, but not COL1A1and COL3A1. In normal culture condition, PTB knockdown suppressed cell proliferation and changed the alternative splicing of some gene related to cell proliferation, however, extracellular matrix expression was not influenced.
2.2The influence of PTB on TGF-β1promoting the expression of genes coding extracellular matrix
Methods:To simulate keloid microenvironment, fibroblasts were cultured in medium containing a different concentration of TGF-β1(Ong/ml,5ng/ml,10ng/ml,20ng/ml). At0,2,6,12,24,48h following TGF-β1treatment, the expression of PTB and extracellular matrix was determined. In the condition of TGF-β1, PTB was also knockdown and extracellular matrix was detected following PTB knockdown.
Results:In fibroblasts from keloid tissues, TGF-β1promoted PTB, COL1A1, FN1and ACTA2expression, as well as the function of TGF-β1was concentration and time dependent. In fibroblasts from normal skin, TGF-β1promoted PTB, COL1A1, FN1and ACTA2expression, however which was not obvious as that in fibroblasts from keloid tissues. In TGF-β1culture condition, PTB knockdown suppressed FN1expression.
2.3The influence of PTB knockdown on transplanted keloid
Methods:To confirm whether PTB is a potential therapeutic target for keloid, we transplanted keloid tissues into nude mice to establish an animal model for keloid. PTB siRNA and control siRNA were injected into transplants, twice a week, for four weeks. After four weeks, transplants were harvested and weighed. The histology of transplants was observed, while PTB and extracelluar matrix expression were valuated.
Results:The weight of transplants from PTB siRNA group was less than control siRNA group. Histologically, there was less cells and III type collagen fibres in transplants from PTB siRNA group. Real time PCR results show PTB, COL3A1and FN1expression were downregulated in PTB siRNA group.
Conclusion:
1. The anti-hnRNPA2Bl titer was firstly found elevated in sera from keloid patients, with immune complex deposits and CD20+B lymphocyte based on immune cell infiltration detected in keloid tissues. These findings suggest that keloid is a fibrotic skin disease mediated by autoimmune responses.
2. PTB increased in tissues and fibroblasts from keloid. PTB knockdown suppressed fibroblasts proliferation in normal culture condition and downregulated FN1expression in TGF-β1culture condition. In keloid transplanted nude mice model, PTB knockdown suppressed COL3A1and FN1expression and accelerated transplants regression. These results suggest PTB may involve in keloid development and been a potential therapeutic target for keloids.
引文
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