巨噬细胞增强表达诱骗受体IL-13Rα2及其在血吸虫病免疫病理调节中作用
|
摘要
IL-13(Interleukin-13)及其受体IL-13Rα2(IL-13 receptor alpha2)是近年血吸虫病、哮喘等纤维化疾病研究“热点”分子。IL-13主要由活化Th2细胞产生,它有两种亲合力和功能截然不同的受体IL-13Rα1和IL-13Rα2,低亲和力IL-13Rα1可结合IL-4Rα形成异源二聚体、活化IL-13信号通路而发挥生物学效应。相反,IL-13Rα2虽能强力结合IL-13,并且是其细胞内吞所需亚单位,但无信号级连效应,又被称为“诱骗受体(decoy receptor)”。IL-13Rα2或重组sIL-13Rα2-Fc融合蛋白(soluble IL-13Rα2-Fc fusion protein)具有高亲和力拮抗IL-13活性作用,对于某些高表达IL-13受体的肿瘤细胞,利用IL-13运载毒性蛋白IL-13-PE38QQR或高亲和力拮抗剂sIL-13Rα2的受体定点靶向作用,实现对肿瘤细胞特异性“杀死”,目前IL-13Rα2肿瘤基因治疗已进入临床前期实验。
IL-13是纤维化细胞外基质重要调节剂,它可直接刺激成纤维细胞产生胶原、导致纤维化,而不影响炎性肉芽肿的形成。目前各种慢性炎性纤维化疾病仍无特效治疗药物,有关IL-13功能和活性及其调节机制的研究将为纤维化疾病干预提供新思路。
鼠血吸虫病作为Th2免疫偏移疾病研究模型,IL-13是血吸虫病纤维化最重要介质,曼氏血吸虫病患者及感染动物血清IL-13Rα2水平升高,IL-13Rα2基因敲除鼠( IL-13Rα2-deficient mice, IL-13Rα2-/- )呈程度加重的纤维化,给予注射sIL-13Rα2-Fc后可明显改善纤维化程度,表明纤维化程度加重与IL-13活性增高有关。IL-13Rα2具有下调曼氏血吸虫肉芽肿炎性反应、延长感染鼠寿命等保护性作用。鉴于曼氏血吸虫与日本血吸虫病理机理不尽相同,有关日本血吸虫病IL-13Rα2的研究尚未见报道。更重要的是,Th2细胞因子通过细胞膜上受体实现信号传递,血吸虫感染的机体IL-13应答细胞及其生物学效应尚未阐明。本课题首先以鼠动物模型研究日本血吸虫病感染过程IL-13Rα2表达水平;进一步建立日本血吸虫感染BALB/C鼠巨噬细胞失活模型,通过研究巨噬细胞失活后IL-13Rα2表达变化及肝脏病理改变,探讨肉芽肿IL-13Rα2阳性表达细胞及其免疫病理调节作用。我们的研究内容主要包括二部分:
1.日本血吸虫感染诱导小鼠诱骗受体IL-13Rα2表达水平升高
采用经腹部皮肤人工感染活尾蚴方法,建立BALB/C鼠日本血吸虫病模型,ELISA法检测血清可溶性IL-13Rα2蛋白动态水平;以IL-13Rα2核苷酸序列(小鼠Accession number NM008356)cDNA为模板设计、合成引物,RT-PCR法扩增肝组织IL-13Rα2基因,获取目的片段;Western blotting检测同期肝组织蛋白表达情况。结果表明:感染鼠血清IL-13Rα2可溶性蛋白水平明显升高,感染后6周达高峰,其后略有下降;PCR法从感染鼠肝脏扩增出胞外区IL-13Rα2 mRNA 800bp片段;Western blotting检测结果显示,肝脏出现特异性IL-13Rα2蛋白条带,相对分子量位于35-49KD之间。因此,日本血吸虫感染诱导机体IL-13Rα2基因转录和蛋白表达增强。
2.肉芽肿巨噬细胞特异性增强表达IL-13Rα2及其免疫病理调节作用
1)体外实验检测巨噬细胞IL-13Rα2表达水平
分离、培养腹腔巨噬细胞,Real time PCR法分析感染鼠巨噬细胞IL-13Rα2 mRNA水平变化(与正常对照组比较);免疫荧光双标法检测IL-13Rα2与CD68共表达情况。结果表明:感染鼠巨噬细胞IL-13Rα2、collagen ?基因水平分别是正常鼠6倍、2.5倍,差异具有显著性(P <0. 01)。细胞免疫荧光染色显示,IL-13Rα2与巨噬细胞标志蛋白CD68呈一致性共表达。体外实验证明:血吸虫感染鼠腹腔巨噬细胞是IL-13Rα2阳性表达细胞。
2)体内实验清除IL-13Rα2阳性巨噬细胞具有下调肉芽肿炎性反应和抑制纤维化作用
进一步我们给感染血吸虫病BALB/C鼠多次尾静脉注射巨噬细胞清除剂GdCl3,建立巨噬细胞失活日本血吸虫病模型,于感染后42天行门静脉灌流术分离肝脏,对肝组织进行目的基因和组织形态学研究。根据荧光镜下肝肉芽肿ED1免疫阳性信号消失判定模型的成功。其后,三重荧光标记法检测ED1阳性细胞与IL-13Rα2阳性细胞的一致性分布以及TaqManPCR分析基因水平差异情况。结果表明:IL-13Rα2在肉芽肿巨噬细胞特异性增强表达;IL-13Rα2阳性巨噬细胞的消失或失活,小鼠肝脏肉芽肿炎性反应减轻,同期纤维化程度降低。综合我们的研究资料,支持以下结论:
日本血吸虫感染诱导机体IL-13Rα2基因转录和蛋白表达增强。肉芽肿巨噬细胞特异性增强表达IL-13Rα2蛋白。清除IL-13Rα2阳性巨噬细胞具有降低肉芽肿炎性反应和减轻纤维化作用,IL-13Rα2+巨噬细胞具有调节肉芽肿免疫病理等重要作用。因此,巨噬细胞增强表达诱骗受体IL-13Rα2可能是血吸虫病肉芽肿及纤维化病理重要调节分子,为Th2相关纤维化疾病基因治疗和侯选细胞靶标的筛选等提供理论依据。
Interleukin (IL)-13 and IL-13 receptor (R)α2 appear to play a major role in tissue fibrosis of schistosomiasis and asthma. IL-13 is produced by T helper 2 (Th2) cells. The two binding receptor chains for IL-13 include IL-13Rα1 and IL-13Rα2. When expressed alone, IL-13Rα1 binds IL-13 with low affinity. However, when IL-13Rα1 is coexpressed with IL-4Rα, a high-affinity heterodimerized receptor is formed, regulating the biological activity of IL-13. In contrast, IL-13Rα2, an essential component for binding and internalization of IL-13 but not for IL-13-induced signal transduction, binds IL-13 with high affinity and is known as the decoy receptor. IL-13Rα2 or sIL-13Rα2-Fc fusion protein is highly inhibition of IL-13 activity. To target IL-13 receptor-positive tumor cells, a recombinant fusion IL-13 cytotoxin termed IL-13-PE38QQR or IL-13-PE was developed. It has been shown that IL-13 cytotoxin induces apoptotic cell death in tumor cells. IL-13Rα2 chain is targeted with a receptor-directed cytotoxin of IL-13-PE to induce specific killing in cancer cells. Based on these experimental results, clinical trials of IL-13Rα2 cancer therapy have been initiated.
IL-13 is a key regulator of the extracellular matrix. It stimulates collagen production in fibroblasts. Its effects on fibrosis are direct with no effect on granuloma size. Elucidating the mechanisms leading to pathology and fibrosis may lead to more effective strategies for immunological intervention in a variety of chronic diseases. Biological activity and regulation of production and function of IL-13 have become an intensive area of research.
IL-13 also plays an important role in schistosomiasis pathogenesis. Serum levels of IL-13Rα2 in both human and mice were upregulated in Schistosoma mansoni (S. mansoni). IL-13Rα2-deficient mice (IL-13Rα2-/-) had a marked exacerbation in hepatic fibrosis. Pathology was prevented when IL-13Rα2-deficient mice were treated with a soluble IL-13Rα2-Fc construct, demonstrating that their exacerbated fibrotic response was due to increased IL-13 activity. IL-13Rα2 down-modulates granulomatous inflammation and prolongs host survival in schistosomiasis. However, much less is known about IL-13Rα2 in S. japonicum, particularly given the difference in the pathology of S. mansoni and S. japonicum. Because Th2 cytokines must bind to their receptors to induce biological responses, the responding cells of IL-13 and the functional activity of IL-13 are unclear. The aim of the present study is to determine in S. japonicum-infected mice: (1) whether the expression of IL-13Rα2 is inducible in a manner similar to that described in S. mansoni studies, and (2) the expression of IL-13Rα2 in macrophages and its effects on immunopathogenesis of schistosomiasis.
The main contents are divided into two sections, as follows:
1. Enhanced expression of IL-13Rα2 mRNA and protein in S. japonicum mice
We exposed a large number of mice to cercariae and established S. japonicum mouse model. Serum levels of IL-13Rα2 at 6、8、and 12 weeks postinfection were examined with ELISA. Using the Primer Express Software v5.0 with mouse IL-13Rα2 sequence obtained from GenBank (Accession number NM008356), PCR primers were designed and synthesized. IL-13Rα2 mRNA and protein in liver tissues were determined by RT-PCR and immunoblotting analysis, respectively. Result: ELISA revealed that serum levels of soluble IL-13Rα2 were significantly elevated at all time points after infection. The peak levels were at 6 weeks postinfection. 800 bp of IL-13Rα2 cDNA was amplified in whole liver tissues from the infected mice. A specific band of IL-13Rα2 protein between 35-49 KD was detected in the same samples. Hence, the decoy receptor (IL-13Rα2) mRNA and protein in S. japonicum mice were elevated.
2. Enhanced expression of IL-13Rα2 in macrophages and its effects in immunopathogenesis of schistosomiasis
1) Identification of IL-13Rα2 expression in macrophages in vitro
Peritoneal macrophages of infected mice (8 weeks postinfection) or uninfected mice were isolated. RNA was extracted and analyzed using TaqMan PCR. IL-13Rα2 expression in macrophages was performed by the double-labelled fluorescent immunocytochemistry technique with primary antibody of goat anti-mouse IL-13Rα2 antibody and monoclonal anti-CD68 antibody, ED1. The results showed that the level of IL-13Rα2 mRNA was markedly (6-fold) enhanced in infected mice compared to that in uninfected mice. In addition, collagen ? gene was 2.5-fold higher in infected mice relative to healthy controls. As indicated by immunocytochemical staining, IL-13Rα2 was expressed in ED1 positive macrophages. These experiments confirmed the production of IL-13Rα2 by ED1 positive macrophages in schistosomiasis. Hence an enhanced expression of IL-13Rα2 was further demonstrated in primary macrophages of murine schistosomiasis.
2) Inactivation of IL-13Rα2 expressing macrophages down-modulates granulomatous inflammation in vivo
We treated mice of schistosomiasis with GdCl3, a reported macrophage depletion reagent. A macrophage-inactivated S. japonicum-infected mouse model was successfully established. Whole liver from each mouse was prepared following perfusion of blood with PBS at 42 days postinfection. Tristain immunofluorescence and TaqMan PCR were used to detect the coexpression of IL-13Rα2 and the macrophage marker (ED1) in liver tissues. These experiments confirmed specifically enhanced expression of IL-13Rα2 in the macrophages of schistosomiasis. Inactivation of IL-13Rα2 expressing macrophages accordingly down-modulates granulomatous inflammation and inhibits fibrosis. Our major findings are summarized below:
Expression of the decoy receptor IL-13Rα2 in S. japonicum mice was increased. Specifically enhanced expression of IL-13Rα2 in macrophages of schistosomiasis was confirmed. Inactivation of IL-13Rα2 expressing macrophages down-modulates granulomatous inflammation and inhibits fibrosis. Hence IL-13Rα2 expressed in macrophages may be a critical contributor to the immunopathogenesis of schistosomiasis. Our data highlight the potential importance of IL-13 signaling and antifibrotic therapeutics in Th2-mediated immune diseases.
IL-13是纤维化细胞外基质重要调节剂,它可直接刺激成纤维细胞产生胶原、导致纤维化,而不影响炎性肉芽肿的形成。目前各种慢性炎性纤维化疾病仍无特效治疗药物,有关IL-13功能和活性及其调节机制的研究将为纤维化疾病干预提供新思路。
鼠血吸虫病作为Th2免疫偏移疾病研究模型,IL-13是血吸虫病纤维化最重要介质,曼氏血吸虫病患者及感染动物血清IL-13Rα2水平升高,IL-13Rα2基因敲除鼠( IL-13Rα2-deficient mice, IL-13Rα2-/- )呈程度加重的纤维化,给予注射sIL-13Rα2-Fc后可明显改善纤维化程度,表明纤维化程度加重与IL-13活性增高有关。IL-13Rα2具有下调曼氏血吸虫肉芽肿炎性反应、延长感染鼠寿命等保护性作用。鉴于曼氏血吸虫与日本血吸虫病理机理不尽相同,有关日本血吸虫病IL-13Rα2的研究尚未见报道。更重要的是,Th2细胞因子通过细胞膜上受体实现信号传递,血吸虫感染的机体IL-13应答细胞及其生物学效应尚未阐明。本课题首先以鼠动物模型研究日本血吸虫病感染过程IL-13Rα2表达水平;进一步建立日本血吸虫感染BALB/C鼠巨噬细胞失活模型,通过研究巨噬细胞失活后IL-13Rα2表达变化及肝脏病理改变,探讨肉芽肿IL-13Rα2阳性表达细胞及其免疫病理调节作用。我们的研究内容主要包括二部分:
1.日本血吸虫感染诱导小鼠诱骗受体IL-13Rα2表达水平升高
采用经腹部皮肤人工感染活尾蚴方法,建立BALB/C鼠日本血吸虫病模型,ELISA法检测血清可溶性IL-13Rα2蛋白动态水平;以IL-13Rα2核苷酸序列(小鼠Accession number NM008356)cDNA为模板设计、合成引物,RT-PCR法扩增肝组织IL-13Rα2基因,获取目的片段;Western blotting检测同期肝组织蛋白表达情况。结果表明:感染鼠血清IL-13Rα2可溶性蛋白水平明显升高,感染后6周达高峰,其后略有下降;PCR法从感染鼠肝脏扩增出胞外区IL-13Rα2 mRNA 800bp片段;Western blotting检测结果显示,肝脏出现特异性IL-13Rα2蛋白条带,相对分子量位于35-49KD之间。因此,日本血吸虫感染诱导机体IL-13Rα2基因转录和蛋白表达增强。
2.肉芽肿巨噬细胞特异性增强表达IL-13Rα2及其免疫病理调节作用
1)体外实验检测巨噬细胞IL-13Rα2表达水平
分离、培养腹腔巨噬细胞,Real time PCR法分析感染鼠巨噬细胞IL-13Rα2 mRNA水平变化(与正常对照组比较);免疫荧光双标法检测IL-13Rα2与CD68共表达情况。结果表明:感染鼠巨噬细胞IL-13Rα2、collagen ?基因水平分别是正常鼠6倍、2.5倍,差异具有显著性(P <0. 01)。细胞免疫荧光染色显示,IL-13Rα2与巨噬细胞标志蛋白CD68呈一致性共表达。体外实验证明:血吸虫感染鼠腹腔巨噬细胞是IL-13Rα2阳性表达细胞。
2)体内实验清除IL-13Rα2阳性巨噬细胞具有下调肉芽肿炎性反应和抑制纤维化作用
进一步我们给感染血吸虫病BALB/C鼠多次尾静脉注射巨噬细胞清除剂GdCl3,建立巨噬细胞失活日本血吸虫病模型,于感染后42天行门静脉灌流术分离肝脏,对肝组织进行目的基因和组织形态学研究。根据荧光镜下肝肉芽肿ED1免疫阳性信号消失判定模型的成功。其后,三重荧光标记法检测ED1阳性细胞与IL-13Rα2阳性细胞的一致性分布以及TaqManPCR分析基因水平差异情况。结果表明:IL-13Rα2在肉芽肿巨噬细胞特异性增强表达;IL-13Rα2阳性巨噬细胞的消失或失活,小鼠肝脏肉芽肿炎性反应减轻,同期纤维化程度降低。综合我们的研究资料,支持以下结论:
日本血吸虫感染诱导机体IL-13Rα2基因转录和蛋白表达增强。肉芽肿巨噬细胞特异性增强表达IL-13Rα2蛋白。清除IL-13Rα2阳性巨噬细胞具有降低肉芽肿炎性反应和减轻纤维化作用,IL-13Rα2+巨噬细胞具有调节肉芽肿免疫病理等重要作用。因此,巨噬细胞增强表达诱骗受体IL-13Rα2可能是血吸虫病肉芽肿及纤维化病理重要调节分子,为Th2相关纤维化疾病基因治疗和侯选细胞靶标的筛选等提供理论依据。
Interleukin (IL)-13 and IL-13 receptor (R)α2 appear to play a major role in tissue fibrosis of schistosomiasis and asthma. IL-13 is produced by T helper 2 (Th2) cells. The two binding receptor chains for IL-13 include IL-13Rα1 and IL-13Rα2. When expressed alone, IL-13Rα1 binds IL-13 with low affinity. However, when IL-13Rα1 is coexpressed with IL-4Rα, a high-affinity heterodimerized receptor is formed, regulating the biological activity of IL-13. In contrast, IL-13Rα2, an essential component for binding and internalization of IL-13 but not for IL-13-induced signal transduction, binds IL-13 with high affinity and is known as the decoy receptor. IL-13Rα2 or sIL-13Rα2-Fc fusion protein is highly inhibition of IL-13 activity. To target IL-13 receptor-positive tumor cells, a recombinant fusion IL-13 cytotoxin termed IL-13-PE38QQR or IL-13-PE was developed. It has been shown that IL-13 cytotoxin induces apoptotic cell death in tumor cells. IL-13Rα2 chain is targeted with a receptor-directed cytotoxin of IL-13-PE to induce specific killing in cancer cells. Based on these experimental results, clinical trials of IL-13Rα2 cancer therapy have been initiated.
IL-13 is a key regulator of the extracellular matrix. It stimulates collagen production in fibroblasts. Its effects on fibrosis are direct with no effect on granuloma size. Elucidating the mechanisms leading to pathology and fibrosis may lead to more effective strategies for immunological intervention in a variety of chronic diseases. Biological activity and regulation of production and function of IL-13 have become an intensive area of research.
IL-13 also plays an important role in schistosomiasis pathogenesis. Serum levels of IL-13Rα2 in both human and mice were upregulated in Schistosoma mansoni (S. mansoni). IL-13Rα2-deficient mice (IL-13Rα2-/-) had a marked exacerbation in hepatic fibrosis. Pathology was prevented when IL-13Rα2-deficient mice were treated with a soluble IL-13Rα2-Fc construct, demonstrating that their exacerbated fibrotic response was due to increased IL-13 activity. IL-13Rα2 down-modulates granulomatous inflammation and prolongs host survival in schistosomiasis. However, much less is known about IL-13Rα2 in S. japonicum, particularly given the difference in the pathology of S. mansoni and S. japonicum. Because Th2 cytokines must bind to their receptors to induce biological responses, the responding cells of IL-13 and the functional activity of IL-13 are unclear. The aim of the present study is to determine in S. japonicum-infected mice: (1) whether the expression of IL-13Rα2 is inducible in a manner similar to that described in S. mansoni studies, and (2) the expression of IL-13Rα2 in macrophages and its effects on immunopathogenesis of schistosomiasis.
The main contents are divided into two sections, as follows:
1. Enhanced expression of IL-13Rα2 mRNA and protein in S. japonicum mice
We exposed a large number of mice to cercariae and established S. japonicum mouse model. Serum levels of IL-13Rα2 at 6、8、and 12 weeks postinfection were examined with ELISA. Using the Primer Express Software v5.0 with mouse IL-13Rα2 sequence obtained from GenBank (Accession number NM008356), PCR primers were designed and synthesized. IL-13Rα2 mRNA and protein in liver tissues were determined by RT-PCR and immunoblotting analysis, respectively. Result: ELISA revealed that serum levels of soluble IL-13Rα2 were significantly elevated at all time points after infection. The peak levels were at 6 weeks postinfection. 800 bp of IL-13Rα2 cDNA was amplified in whole liver tissues from the infected mice. A specific band of IL-13Rα2 protein between 35-49 KD was detected in the same samples. Hence, the decoy receptor (IL-13Rα2) mRNA and protein in S. japonicum mice were elevated.
2. Enhanced expression of IL-13Rα2 in macrophages and its effects in immunopathogenesis of schistosomiasis
1) Identification of IL-13Rα2 expression in macrophages in vitro
Peritoneal macrophages of infected mice (8 weeks postinfection) or uninfected mice were isolated. RNA was extracted and analyzed using TaqMan PCR. IL-13Rα2 expression in macrophages was performed by the double-labelled fluorescent immunocytochemistry technique with primary antibody of goat anti-mouse IL-13Rα2 antibody and monoclonal anti-CD68 antibody, ED1. The results showed that the level of IL-13Rα2 mRNA was markedly (6-fold) enhanced in infected mice compared to that in uninfected mice. In addition, collagen ? gene was 2.5-fold higher in infected mice relative to healthy controls. As indicated by immunocytochemical staining, IL-13Rα2 was expressed in ED1 positive macrophages. These experiments confirmed the production of IL-13Rα2 by ED1 positive macrophages in schistosomiasis. Hence an enhanced expression of IL-13Rα2 was further demonstrated in primary macrophages of murine schistosomiasis.
2) Inactivation of IL-13Rα2 expressing macrophages down-modulates granulomatous inflammation in vivo
We treated mice of schistosomiasis with GdCl3, a reported macrophage depletion reagent. A macrophage-inactivated S. japonicum-infected mouse model was successfully established. Whole liver from each mouse was prepared following perfusion of blood with PBS at 42 days postinfection. Tristain immunofluorescence and TaqMan PCR were used to detect the coexpression of IL-13Rα2 and the macrophage marker (ED1) in liver tissues. These experiments confirmed specifically enhanced expression of IL-13Rα2 in the macrophages of schistosomiasis. Inactivation of IL-13Rα2 expressing macrophages accordingly down-modulates granulomatous inflammation and inhibits fibrosis. Our major findings are summarized below:
Expression of the decoy receptor IL-13Rα2 in S. japonicum mice was increased. Specifically enhanced expression of IL-13Rα2 in macrophages of schistosomiasis was confirmed. Inactivation of IL-13Rα2 expressing macrophages down-modulates granulomatous inflammation and inhibits fibrosis. Hence IL-13Rα2 expressed in macrophages may be a critical contributor to the immunopathogenesis of schistosomiasis. Our data highlight the potential importance of IL-13 signaling and antifibrotic therapeutics in Th2-mediated immune diseases.
引文
1.高桂华.哮喘病人增加的原因,国外医学·社会医学分册. 2004;21:181-182.
2.陈育智,马煜等2000年全国31省市40万0～14岁儿童哮喘患病情况调查及与1990年同类调查对比研究医学研究杂志.2006;35:44-45.
3. Scrivener S, Yemaneberhan H, Zebenigus M, Tilahun D, Girma S, Ali S, et al. Independent effect s of intestinal parasite infection and domestic allergen exposure on risk of wheeze in Ethiopia: a nested case-control study. Lancet. 2001;358:1493-1499.
4. Anthony, R. Protective immune mechanisms in helminth infection. Nature Rev Immuno. 2007;7:975-987.
5. Wilson MS, Maizels RM. Regulation of allergy and autoimmunity in helminth infection. Clin Rev Allergy Immunol. 2004; 26:35-50.
6. Fallon PG, Mangan NE. Suppression of TH2-type allergic reactions by helminth infection. Nature Rev Immunol. 2007;7:220-230.
7y. Wynn TA. IL-13 effector functions. Ann Rev Immunol. 2003;21:425-456.
8all. Doherty TM, Kastelein R, Menon S, Andrade S, Coffman RL. Modulation of murine macrophage function by IL-13. J Immunol. 1993;151:7151-7160.
9. Boulay JL, Paul WE. The interleukin-4 family of lymphokines. Curr Opion Immunol 1992;4:294-298.
10. Donaldson DD, Whitters MJ, Fitz LJ, Neben TY, Finnerty H, Henderson SL, et al. The murine IL-13 receptor alpha 2: molecular cloning, characterization, and comparison with murine IL-13 receptor alpha 1. J Immunol. 1998;161:2317–2324.
11. Bernard J, Treton D, Vermot-Desroches C, Boden C, Horellou P, et al. Expression of interleukine 13 receptor in glioma and renal cell carcinoma: IL13Ralpha2 as a decoy receptor for IL13. Lab Invest. 2001;81:1223-1231.
12. Feng N, Lugli SM, Schnyder B, et al. The interleukine-4/interleukine-13 receptor ofhuman synovial fibroblasts: overexpression of the nonsignaling interleukine-13 receptorα2. Lab Invest. 1998;78:591-602.
13. Zhang JG, Hilton DJ, Willson TA, McFarlane C, Roberts BA, Moritz RL, et al. Identification, purification, and characterization of a soluble interleukin IL-13-binding protein. Evidence that it is distinct from the cloned IL-13 receptor and IL-4 receptor alpha-chains. J Biol Chem. 1997; 272:9474–9480.
14. Daines MO, Hershey GK. A novel mechanism by which interferon-gamma can regulate interleukin (IL)-13 responses. Evidence for intracellular stores of IL-13 receptor alpha-2 and their rapid mobilization by interferon-gamma. J Biol Chem. 2002; 277:10387–10393.
15. Kawakami K, Taguchi J, Murata T, Puri RK. The interleukin-13 receptor alpha2 chain: an essential component for binding and internalization but not for interleukin-13-induced signal transduction through the STAT6 pathway. Blood. 2001; 97:2673-2679.
16. Kawakami K, Kawakami M, Puri RK. Specifically targeted killing of interleukin-13 (IL-13) receptor-expressing breast cancer by IL-13 fusion cytotoxin in animal model of human disease. Mol Cancer Ther. 2004; 3:137-147.
17. Kawakami K. Cancer gene therapy utilizing interleukin-13 receptorα2 chain. Curr Gene Ther. 2005;5:213–223. 18all. Modolell M, Corraliza IM, Link F, Soler G, Eichmann K. Reciprocal regulation of the nitric oxide synthase/arginase balance in mouse bone marrow-derived macrophages by TH1 and TH2 cytokines. Eur J Immunol.1995;25:1101-1104.
19. Dessein A, Kouriba B, Eboumbou C, Dessein H, Argiro L, et al. Interleukin-13 in the skin and interferon-gamma in the liver are key players in immune protection in human schistosomiasis. Immunol Rev. 2004;201:180-190.
20. Goerdt S, Orfanos CE. Other functions, other genes:alternative activation of antigen-presenting cells. Immunity. 1999;10:137-142.
21. Chiaramonte MG, Donaldson DD, Cheever AW, Wynn TA. An IL-13 inhibitor blocks the development of hepatic fibrosisi during a T-helper type 2-dominated inflammatory response. J Clin Invest. 1999;104:777-785.
22. Fichtner-Feigl S, Strober W, Kawakami K, Puri RK, Kitani A. IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis. Nat Med. 2006;12:99-106.
23. Dunne DW, Cooke A. (2005) A worm's eye view of the immune system: consequences for evolution of human autoimmune disease. Nat Rev Immunol. 2005;5:420-426.
24.夏超明,龚唯,骆伟等日本血吸虫感染小鼠肝肉芽肿与Th1/ Th2细胞因子水平的动态变化.复旦学报(医学科学版).2001;28:39-41.
25. Kaplan MH, Whitfield JR, Boros DL, Grusby MJ. Th2 cells are required for the Schistosoma mansoni egg-induced granulomatous response. J Immunol. 1998;160: 1850-1856.
26. Pearce EJ, MacDonald AS. The immunobiology of schistosomiasis. Nat Rev Immunol. 2002;2:499-511.
27. Alpini G, Phillips JO, Vroman B, LaRusso NF. Recent advances in the isolation of liver cells. Hepatology. 1994;20:494-514.
28. Strachan DP. Family size, infection and atopy: the first decade of the“hygiene hypothesis”. Thorax. 2000;55 Suppl1:S2-10.
29all. Palmer LJ, Celedón JC, Weiss ST, Wang B, Fang Z, Xu X. Ascaria lumbricoides infection is associated with increased risk of childhood asthma and atopy in rural China. Am J Respir Crit Care Med. 2002;165:1489-1493.
30. Van den Biggelaar AH, van Ree R, Rodrigues LC, Lell B, Deelder AM, et al. Decreased atopy in children infected with Schistosoma haematobium: a role for parasite-induced interleukin-10. Lancet. 2000;356:1723-1727.
31. Araujo MI, Lopes AA, Medeiros M, Cruz AA, Sousa-Atta L, et al. Inverseassociation between skin response to aeroallergens and Schistosoma mansoni infection. Int Arch Allergy Immunol. 2000;123:145-148.
32. Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214: 199–210.
33. Ragheb S, Boros DL. Characterization of granuloma T lymphocyte function from Schistosoma mansoni-infected mice. J Immunol. 1989;142:3239–3246.
34. Bilzer M, Roggel F, Gerbes AL. Role of Kupffer cells in host defense and liver disease. Liver Int. 2006;26:1175–1186.
35. Mentink-Kane MM, Cheever AW, Thompson RW, Hari DM, Kabatereine NB, Vennervald BJ, et al. IL-13 receptor alpha 2 down-modulates granulomatous inflammation and prolongs host survival in schistosomiasis. Pron Natl Acad Sci USA. 2004;101:586–590.
36. Kruys V, Marinx O, Shaw G, Deschamps J, Huez G. Translational blockade imposed by cytokine-derived UA-rich sequences. Science. 1989;245:852–855.
37. Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest. 2005;115:56-65.
38. Benoit M, Desnues B, Mege JL. (2008) Macrophage Polarization in Bacterial Infections. J Immunol. 2008;181:3733-3739.
39all. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23:549-555.
40. Russell DG. (2007) Who puts the tubercle in tuberculosis? Nat Rev Microbiol. 2007;5:39-47.
41. Reese TA, Liang HE, Tager AM, Luster AD, Van Rooijen N, et al. Chitin induces accumulation in tissue of innate immune cells associated with allergy. Nature. 2007;447:92-96.
42. Herbert DR, H?lscher C, Mohrs M, Arendse B, Schwegmann A, et al. Alternative Macrophage Activation Is Essential for Survival during Schistosomiasis and Downmodulate T Helper 1 Responses and Immunopathology. Immunity. 2004;20: 623-635.
43. Martin P, Leibovich SJ. Inflammatory cells during wound repair: the good, the bad and the ugly. Trends Cell Biol. 2005;15:599-607.
44. Sandler NG, Mentink-Kane MM, Cheever AW, Wynn TA.. Global gene expression profiles during acute pathogen-induced pulmonary inflammation reveal divergent roles for Th1 and Th2 responses in tissue repair. J Immunol. 2003;171:3655-3667.
45. Anthony RM, Urban JF Jr, Alem F, Hamed HA, Rozo CT, et al. Memory T(H)2 cells induce alternatively activated macrophages to mediate protection against nematode parasites. Nat Med. 2006;12:955-960.
46. Da Silva RP, Gordon S. Phagocytosis stimulates alternative glycosylation of macrosialin (mouse CD68), a macrophage-specific endosomal protein. Biochem J. 1999; 338:687-694.
47. Dijkstra CD, D?pp EA, Joling P, Kraal G. The heterogeneity of mononuclear phagocytes in lymphoid organs: distinct macrophage subpopulations in the rat recognized by mononuclear antibodies ED1, ED2 and ED3. Immunology. 1985;54, 589-599.
48. Hardonk MJ, Dijkhuis FW, Hulstaert CE, Koudstaal J. Heterogeneity of rat liver and spleen macrophages in gadolinium chloride-induced elimination and repopulation. J Leukoc Biol. 1992;52:296-302.
49. Slegers TP, van Rooijen N, van Rij G, van der Gaag R. Delayed graft rejection in pre-vascularised corneas after subconjunctival injection of clodronate liposomes. Curr Eye Res. 2000;20:322-324.
50. Jose MD, Ikezumi Y, van Rooijen N, Atkins RC, Chadban SJ. Macrophages act as effectors of tissue damage in acute renal allograft rejection. Transplantation.2003;76:1015-1022.
51. Mizgerd JP, Molina RM, Stearns RC, Brain JD, Warner AE. Gadolinium induces macrophage apoptosis. J Leukoc Biol. 1996;59:189-195.
1.姚希贤,徐克成,编著.肝纤维化的基础与临床.第1版.上海:上海科技教育出版社, 2003: 1-102.
2. Bartley PB, Ramm GA, Jones MK, et al. A contributory role for activated hepatic stellate cells in the dynamics of Schistosoma japonicum egg-induced fibrosis. Intl J Parasitol. 2006;36:993-1001.
3. Parsons CJ, Takashima M, Rippe RA. Molecular mechanisms of hepatic fibrogenesis. J Gastroenterol Hepatol, 2007, 22 Suppl 1: S79-84.
4. Wilson MS, Mentink-Kane MM, Pesce JT, et al. The immunobiology of schistosomiasis. Immunol Cell Bio. 2007 ;85 :148–154.
5. Mentink-kane MM,Wynn TA. Opposing roles for IL-13 and IL-13 receptor alpha 2 in health and disease. Immunol Rev. 2004;202:191-202.
6. Xiong LJ, Zhu JF, Luo DD, et al. Effects of pentoxifylline on the hepatic content of TGF-β1 and collagen in Schistosomiasis japonica mice with liver fibrosi. World J Gastroenterol, 2003;9:152-154.
7. Mentink-Kane MM, Cheever AW, Thompson RW, et al. IL-13 receptor alpha 2 down-modulates granulomatous inflammation and prolongs host survival in schistosomiasis. Proc Natl Acad Sci U S A, 2004;101(2): 586-590.
8. Noel W, Raes G, Hassanzadeh Ghassabeh G, et al. Alternatively activated macrophages during parasite infections. Trends Parasitol. 2004;20:126-133.
9. Chu DY, Li CL, Shen JL, et al.The effect of Paeoniflorin on hepatic histologic immunopathogenesis in mice with Schistosoma Japonica infection. China J Parasitol Parasit Dis. 2008;26:10-15. (in Chinese) (储德勇,李丛磊,沈继龙,等.芍药苷对日本血吸虫感染小鼠肝组织免疫病理的影响[J].中国寄生虫学与寄生虫病杂志, 2008;26:10-15.)
10. Chu DY, Li CL, Shen JL, et al. Effect of paeoniflorin on secretion of TGF-β1 from macrophages in mice. China J Parasitol Parasit Dis 2008, 26(2):81-85.(in Chinese) (储德勇,李丛磊,沈继龙,等.芍药苷对小鼠巨噬细胞分泌TGF-β1的影响[J].中国寄生虫学与寄生虫病杂志, 2008;26:81-85)
11. Gordon S. Alternative activation of macrophages.Nat Rev Immunol. 2003;3: 23-35.
12. Hesse M, Cheever AW, Jankovic D, et al. NOS-2 mediates the protective anti-inflammatory and antifibrotic effects of the Th1-inducing adjuvant, IL-12, in a Th2 model of granulomatous diseas. Am J Pathol. 2000;157:945–955.
13. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-b family signaling. Nature. 2003; 425:577-584.
14. Wynn TA. Cellular and molecular mechanisms of fibrosis.J Pathol. 2008;214: 199–210
15. Wu XL, Zeng WZ, Wang PL. TGF-Smad signaling pathway and in hepatic fibrosis. World Chine J Digestol. 2003;11:1601-1605. (in Chinese) (吴晓玲,曾维政,王丕龙.TGF-Smad信号转导通路与肝纤维化。世界华人消化杂志2003;11:1601-1605.)
16. Kaviratne M, Hesse M, Leusink M, et al. IL-13 activates a mechanism of tissue fibrosis that is completely TGFβ-independent. J Immunol. 2004;173:4020–4029.
17. Wynn TA. IL-13 effector functions. Annu Rev Immunol. 2003;21: 425-456.
18. Chiaramonte MG,Cheever AW,Malley JD,et al. Studies of murine schistosomiasis reveal interleukin-13 blockade as a treatment for established and progressive liver fibrosis. Hepatology. 2001;34:273-282.
19. Takeda K, Akira S. STAT family of transcription factors in cytokine-mediated biological responses. Cytokine Growth FactorRev. 2000;11:199-207.
20. Thomas TM. Decoy receptor springs to life and eases fibrosis. Nat Med. 2006;12: 13-14.
21. Gorelik L, Flavell RA. Transforming growth factor-βin T-cell biology. Nat Rev Immunol. 2002; 2:46-53.
22. Lee CG, Homer RJ, Zhu Z, et al. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factorβ1. J Exp Med, 2001;194:809-821.
23. Vaillant B, Chiaramonte MG, Cheever AW, et al. Regulation of hepatic fibrosis and extracellular matrix genes by the Th response:New insight into the role of tissue inhibitors of matrix metalloproteinases. J Immunol. 2001;167:7017-7026.
24. Nakao A, Miike S, Hatano M, et al. Blockade of transforming growth factor beta/Smad signaling in T cells by overexpression of Smad7 enhances antigen-induced airway inflammation and airway reactivity. J Exp Med. 2000;192:151-158.
25. Shinkai K, Mohrs M, Locksley RM. Helper T cells regulate type-2 innate immunity in vivo. Nature. 2002;420:825-829.
26. Munder M, Eichmann K, Moran JM, et al. Th1/Th2-regulatedexpression of arginase isoforms in murine macrophages and dendritic cells. J Immunol. 1999;163:3771-3777.
27. Lindemann D, Racke K. Glucocorticoid inhibition of interleukin-4 (IL-4) and interleukin-13 (IL-13) induced up-regulation of arginase in rat airway fibroblasts. Naunyn Schmiedebergs Arch Pharmacol. 2003;368:546-550.
28. Hesse M, Modolell M, La Flamme AC, et al. Differential regulation of nitric oxide synthase-2 and arginase-1 by type 1/type 2 cytokines in vivo: granulomatous pathology is shaped by the pattern of L-arginine metabolism. J Immunol. 2001;167:6533-6544.
29. Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature. 1996;383:787-793.
2.陈育智,马煜等2000年全国31省市40万0～14岁儿童哮喘患病情况调查及与1990年同类调查对比研究医学研究杂志.2006;35:44-45.
3. Scrivener S, Yemaneberhan H, Zebenigus M, Tilahun D, Girma S, Ali S, et al. Independent effect s of intestinal parasite infection and domestic allergen exposure on risk of wheeze in Ethiopia: a nested case-control study. Lancet. 2001;358:1493-1499.
4. Anthony, R. Protective immune mechanisms in helminth infection. Nature Rev Immuno. 2007;7:975-987.
5. Wilson MS, Maizels RM. Regulation of allergy and autoimmunity in helminth infection. Clin Rev Allergy Immunol. 2004; 26:35-50.
6. Fallon PG, Mangan NE. Suppression of TH2-type allergic reactions by helminth infection. Nature Rev Immunol. 2007;7:220-230.
7y. Wynn TA. IL-13 effector functions. Ann Rev Immunol. 2003;21:425-456.
8all. Doherty TM, Kastelein R, Menon S, Andrade S, Coffman RL. Modulation of murine macrophage function by IL-13. J Immunol. 1993;151:7151-7160.
9. Boulay JL, Paul WE. The interleukin-4 family of lymphokines. Curr Opion Immunol 1992;4:294-298.
10. Donaldson DD, Whitters MJ, Fitz LJ, Neben TY, Finnerty H, Henderson SL, et al. The murine IL-13 receptor alpha 2: molecular cloning, characterization, and comparison with murine IL-13 receptor alpha 1. J Immunol. 1998;161:2317–2324.
11. Bernard J, Treton D, Vermot-Desroches C, Boden C, Horellou P, et al. Expression of interleukine 13 receptor in glioma and renal cell carcinoma: IL13Ralpha2 as a decoy receptor for IL13. Lab Invest. 2001;81:1223-1231.
12. Feng N, Lugli SM, Schnyder B, et al. The interleukine-4/interleukine-13 receptor ofhuman synovial fibroblasts: overexpression of the nonsignaling interleukine-13 receptorα2. Lab Invest. 1998;78:591-602.
13. Zhang JG, Hilton DJ, Willson TA, McFarlane C, Roberts BA, Moritz RL, et al. Identification, purification, and characterization of a soluble interleukin IL-13-binding protein. Evidence that it is distinct from the cloned IL-13 receptor and IL-4 receptor alpha-chains. J Biol Chem. 1997; 272:9474–9480.
14. Daines MO, Hershey GK. A novel mechanism by which interferon-gamma can regulate interleukin (IL)-13 responses. Evidence for intracellular stores of IL-13 receptor alpha-2 and their rapid mobilization by interferon-gamma. J Biol Chem. 2002; 277:10387–10393.
15. Kawakami K, Taguchi J, Murata T, Puri RK. The interleukin-13 receptor alpha2 chain: an essential component for binding and internalization but not for interleukin-13-induced signal transduction through the STAT6 pathway. Blood. 2001; 97:2673-2679.
16. Kawakami K, Kawakami M, Puri RK. Specifically targeted killing of interleukin-13 (IL-13) receptor-expressing breast cancer by IL-13 fusion cytotoxin in animal model of human disease. Mol Cancer Ther. 2004; 3:137-147.
17. Kawakami K. Cancer gene therapy utilizing interleukin-13 receptorα2 chain. Curr Gene Ther. 2005;5:213–223. 18all. Modolell M, Corraliza IM, Link F, Soler G, Eichmann K. Reciprocal regulation of the nitric oxide synthase/arginase balance in mouse bone marrow-derived macrophages by TH1 and TH2 cytokines. Eur J Immunol.1995;25:1101-1104.
19. Dessein A, Kouriba B, Eboumbou C, Dessein H, Argiro L, et al. Interleukin-13 in the skin and interferon-gamma in the liver are key players in immune protection in human schistosomiasis. Immunol Rev. 2004;201:180-190.
20. Goerdt S, Orfanos CE. Other functions, other genes:alternative activation of antigen-presenting cells. Immunity. 1999;10:137-142.
21. Chiaramonte MG, Donaldson DD, Cheever AW, Wynn TA. An IL-13 inhibitor blocks the development of hepatic fibrosisi during a T-helper type 2-dominated inflammatory response. J Clin Invest. 1999;104:777-785.
22. Fichtner-Feigl S, Strober W, Kawakami K, Puri RK, Kitani A. IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis. Nat Med. 2006;12:99-106.
23. Dunne DW, Cooke A. (2005) A worm's eye view of the immune system: consequences for evolution of human autoimmune disease. Nat Rev Immunol. 2005;5:420-426.
24.夏超明,龚唯,骆伟等日本血吸虫感染小鼠肝肉芽肿与Th1/ Th2细胞因子水平的动态变化.复旦学报(医学科学版).2001;28:39-41.
25. Kaplan MH, Whitfield JR, Boros DL, Grusby MJ. Th2 cells are required for the Schistosoma mansoni egg-induced granulomatous response. J Immunol. 1998;160: 1850-1856.
26. Pearce EJ, MacDonald AS. The immunobiology of schistosomiasis. Nat Rev Immunol. 2002;2:499-511.
27. Alpini G, Phillips JO, Vroman B, LaRusso NF. Recent advances in the isolation of liver cells. Hepatology. 1994;20:494-514.
28. Strachan DP. Family size, infection and atopy: the first decade of the“hygiene hypothesis”. Thorax. 2000;55 Suppl1:S2-10.
29all. Palmer LJ, Celedón JC, Weiss ST, Wang B, Fang Z, Xu X. Ascaria lumbricoides infection is associated with increased risk of childhood asthma and atopy in rural China. Am J Respir Crit Care Med. 2002;165:1489-1493.
30. Van den Biggelaar AH, van Ree R, Rodrigues LC, Lell B, Deelder AM, et al. Decreased atopy in children infected with Schistosoma haematobium: a role for parasite-induced interleukin-10. Lancet. 2000;356:1723-1727.
31. Araujo MI, Lopes AA, Medeiros M, Cruz AA, Sousa-Atta L, et al. Inverseassociation between skin response to aeroallergens and Schistosoma mansoni infection. Int Arch Allergy Immunol. 2000;123:145-148.
32. Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214: 199–210.
33. Ragheb S, Boros DL. Characterization of granuloma T lymphocyte function from Schistosoma mansoni-infected mice. J Immunol. 1989;142:3239–3246.
34. Bilzer M, Roggel F, Gerbes AL. Role of Kupffer cells in host defense and liver disease. Liver Int. 2006;26:1175–1186.
35. Mentink-Kane MM, Cheever AW, Thompson RW, Hari DM, Kabatereine NB, Vennervald BJ, et al. IL-13 receptor alpha 2 down-modulates granulomatous inflammation and prolongs host survival in schistosomiasis. Pron Natl Acad Sci USA. 2004;101:586–590.
36. Kruys V, Marinx O, Shaw G, Deschamps J, Huez G. Translational blockade imposed by cytokine-derived UA-rich sequences. Science. 1989;245:852–855.
37. Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest. 2005;115:56-65.
38. Benoit M, Desnues B, Mege JL. (2008) Macrophage Polarization in Bacterial Infections. J Immunol. 2008;181:3733-3739.
39all. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23:549-555.
40. Russell DG. (2007) Who puts the tubercle in tuberculosis? Nat Rev Microbiol. 2007;5:39-47.
41. Reese TA, Liang HE, Tager AM, Luster AD, Van Rooijen N, et al. Chitin induces accumulation in tissue of innate immune cells associated with allergy. Nature. 2007;447:92-96.
42. Herbert DR, H?lscher C, Mohrs M, Arendse B, Schwegmann A, et al. Alternative Macrophage Activation Is Essential for Survival during Schistosomiasis and Downmodulate T Helper 1 Responses and Immunopathology. Immunity. 2004;20: 623-635.
43. Martin P, Leibovich SJ. Inflammatory cells during wound repair: the good, the bad and the ugly. Trends Cell Biol. 2005;15:599-607.
44. Sandler NG, Mentink-Kane MM, Cheever AW, Wynn TA.. Global gene expression profiles during acute pathogen-induced pulmonary inflammation reveal divergent roles for Th1 and Th2 responses in tissue repair. J Immunol. 2003;171:3655-3667.
45. Anthony RM, Urban JF Jr, Alem F, Hamed HA, Rozo CT, et al. Memory T(H)2 cells induce alternatively activated macrophages to mediate protection against nematode parasites. Nat Med. 2006;12:955-960.
46. Da Silva RP, Gordon S. Phagocytosis stimulates alternative glycosylation of macrosialin (mouse CD68), a macrophage-specific endosomal protein. Biochem J. 1999; 338:687-694.
47. Dijkstra CD, D?pp EA, Joling P, Kraal G. The heterogeneity of mononuclear phagocytes in lymphoid organs: distinct macrophage subpopulations in the rat recognized by mononuclear antibodies ED1, ED2 and ED3. Immunology. 1985;54, 589-599.
48. Hardonk MJ, Dijkhuis FW, Hulstaert CE, Koudstaal J. Heterogeneity of rat liver and spleen macrophages in gadolinium chloride-induced elimination and repopulation. J Leukoc Biol. 1992;52:296-302.
49. Slegers TP, van Rooijen N, van Rij G, van der Gaag R. Delayed graft rejection in pre-vascularised corneas after subconjunctival injection of clodronate liposomes. Curr Eye Res. 2000;20:322-324.
50. Jose MD, Ikezumi Y, van Rooijen N, Atkins RC, Chadban SJ. Macrophages act as effectors of tissue damage in acute renal allograft rejection. Transplantation.2003;76:1015-1022.
51. Mizgerd JP, Molina RM, Stearns RC, Brain JD, Warner AE. Gadolinium induces macrophage apoptosis. J Leukoc Biol. 1996;59:189-195.
1.姚希贤,徐克成,编著.肝纤维化的基础与临床.第1版.上海:上海科技教育出版社, 2003: 1-102.
2. Bartley PB, Ramm GA, Jones MK, et al. A contributory role for activated hepatic stellate cells in the dynamics of Schistosoma japonicum egg-induced fibrosis. Intl J Parasitol. 2006;36:993-1001.
3. Parsons CJ, Takashima M, Rippe RA. Molecular mechanisms of hepatic fibrogenesis. J Gastroenterol Hepatol, 2007, 22 Suppl 1: S79-84.
4. Wilson MS, Mentink-Kane MM, Pesce JT, et al. The immunobiology of schistosomiasis. Immunol Cell Bio. 2007 ;85 :148–154.
5. Mentink-kane MM,Wynn TA. Opposing roles for IL-13 and IL-13 receptor alpha 2 in health and disease. Immunol Rev. 2004;202:191-202.
6. Xiong LJ, Zhu JF, Luo DD, et al. Effects of pentoxifylline on the hepatic content of TGF-β1 and collagen in Schistosomiasis japonica mice with liver fibrosi. World J Gastroenterol, 2003;9:152-154.
7. Mentink-Kane MM, Cheever AW, Thompson RW, et al. IL-13 receptor alpha 2 down-modulates granulomatous inflammation and prolongs host survival in schistosomiasis. Proc Natl Acad Sci U S A, 2004;101(2): 586-590.
8. Noel W, Raes G, Hassanzadeh Ghassabeh G, et al. Alternatively activated macrophages during parasite infections. Trends Parasitol. 2004;20:126-133.
9. Chu DY, Li CL, Shen JL, et al.The effect of Paeoniflorin on hepatic histologic immunopathogenesis in mice with Schistosoma Japonica infection. China J Parasitol Parasit Dis. 2008;26:10-15. (in Chinese) (储德勇,李丛磊,沈继龙,等.芍药苷对日本血吸虫感染小鼠肝组织免疫病理的影响[J].中国寄生虫学与寄生虫病杂志, 2008;26:10-15.)
10. Chu DY, Li CL, Shen JL, et al. Effect of paeoniflorin on secretion of TGF-β1 from macrophages in mice. China J Parasitol Parasit Dis 2008, 26(2):81-85.(in Chinese) (储德勇,李丛磊,沈继龙,等.芍药苷对小鼠巨噬细胞分泌TGF-β1的影响[J].中国寄生虫学与寄生虫病杂志, 2008;26:81-85)
11. Gordon S. Alternative activation of macrophages.Nat Rev Immunol. 2003;3: 23-35.
12. Hesse M, Cheever AW, Jankovic D, et al. NOS-2 mediates the protective anti-inflammatory and antifibrotic effects of the Th1-inducing adjuvant, IL-12, in a Th2 model of granulomatous diseas. Am J Pathol. 2000;157:945–955.
13. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-b family signaling. Nature. 2003; 425:577-584.
14. Wynn TA. Cellular and molecular mechanisms of fibrosis.J Pathol. 2008;214: 199–210
15. Wu XL, Zeng WZ, Wang PL. TGF-Smad signaling pathway and in hepatic fibrosis. World Chine J Digestol. 2003;11:1601-1605. (in Chinese) (吴晓玲,曾维政,王丕龙.TGF-Smad信号转导通路与肝纤维化。世界华人消化杂志2003;11:1601-1605.)
16. Kaviratne M, Hesse M, Leusink M, et al. IL-13 activates a mechanism of tissue fibrosis that is completely TGFβ-independent. J Immunol. 2004;173:4020–4029.
17. Wynn TA. IL-13 effector functions. Annu Rev Immunol. 2003;21: 425-456.
18. Chiaramonte MG,Cheever AW,Malley JD,et al. Studies of murine schistosomiasis reveal interleukin-13 blockade as a treatment for established and progressive liver fibrosis. Hepatology. 2001;34:273-282.
19. Takeda K, Akira S. STAT family of transcription factors in cytokine-mediated biological responses. Cytokine Growth FactorRev. 2000;11:199-207.
20. Thomas TM. Decoy receptor springs to life and eases fibrosis. Nat Med. 2006;12: 13-14.
21. Gorelik L, Flavell RA. Transforming growth factor-βin T-cell biology. Nat Rev Immunol. 2002; 2:46-53.
22. Lee CG, Homer RJ, Zhu Z, et al. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factorβ1. J Exp Med, 2001;194:809-821.
23. Vaillant B, Chiaramonte MG, Cheever AW, et al. Regulation of hepatic fibrosis and extracellular matrix genes by the Th response:New insight into the role of tissue inhibitors of matrix metalloproteinases. J Immunol. 2001;167:7017-7026.
24. Nakao A, Miike S, Hatano M, et al. Blockade of transforming growth factor beta/Smad signaling in T cells by overexpression of Smad7 enhances antigen-induced airway inflammation and airway reactivity. J Exp Med. 2000;192:151-158.
25. Shinkai K, Mohrs M, Locksley RM. Helper T cells regulate type-2 innate immunity in vivo. Nature. 2002;420:825-829.
26. Munder M, Eichmann K, Moran JM, et al. Th1/Th2-regulatedexpression of arginase isoforms in murine macrophages and dendritic cells. J Immunol. 1999;163:3771-3777.
27. Lindemann D, Racke K. Glucocorticoid inhibition of interleukin-4 (IL-4) and interleukin-13 (IL-13) induced up-regulation of arginase in rat airway fibroblasts. Naunyn Schmiedebergs Arch Pharmacol. 2003;368:546-550.
28. Hesse M, Modolell M, La Flamme AC, et al. Differential regulation of nitric oxide synthase-2 and arginase-1 by type 1/type 2 cytokines in vivo: granulomatous pathology is shaped by the pattern of L-arginine metabolism. J Immunol. 2001;167:6533-6544.
29. Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature. 1996;383:787-793.