比较跨膜型和分泌型TNF-α的体内杀瘤效应及其机制  

Comparison of antitumor effects from transmembrane and secreted TNF-α in vivo

作　　者：李清芬[1] 李卓娅[1] 龚非力[1] 徐勇[1] 姜小丹[1] 熊平[1] 冯玮[1] 

机构地区：[1]华中科技大学同济医学院免疫学教研室,武汉430030

出　　处：《中华微生物学和免疫学杂志》2001年第6期615-618,共4页Chinese Journal of Microbiology and Immunology

基　　金：国家自然科学基金重点资助项目 ( 396 30 32 0 )

摘　　要：目的　比较跨膜型和分泌型TNF α在体内的抗瘤作用及机制。方法　在小鼠接种肿瘤细胞H2 2第 3天 ,于肿瘤接种部位分别皮下注射插入TNF α及其突变体基因的质粒DNA(分泌型TNF突变体、跨膜型TNF突变体和野生型TNF α) ,观察肿瘤的生长情况 ,并用TUNEL检测肿瘤细胞是否发生凋亡 ;用免疫组化检测肿瘤局部淋巴细胞浸润和肿瘤组织表达的Fas和CD44V3。结果　TNF α及其突变体均可被肿瘤细胞有效表达 ,并都可明显抑制肿瘤的生长 (P <0 .0 1) ,其中跨膜型TNF突变体抑瘤作用最强 ,可促进肿瘤表达Fas ,引起肿瘤细胞发生明显凋亡 ,同时抑制其表达CD44V3(P <0 .0 1) ;而分泌型TNF则可诱导肿瘤局部大量淋巴细胞 (CD4+、CD8+)浸润 (P <0 .0 1) ,并引起肿瘤组织出血坏死。结论　直接注射跨膜型和分泌型TNF α裸DNA均可在体内有效杀瘤。跨膜型TNF的体内杀瘤机制可能不同于分泌型TNF ,前者可直接和通过Fas途径间接诱导瘤细胞凋亡 ;Objective To compare the antitumor effects from transmembrane TNF α(TM TNF α) and secreted TNF α (S TNF α) in vivo . Methods Three types of plasmids containing TNF α gene and its two mutants (wild type TNF α, transmembrane TNF α mutant; secreted TNF α mutant) were injected subcutaneously on day 3 after H22 tumor cell challenge. The tumor growth was observed and apoptosis was detected by TUNEL. Lymphocyte infiltration and the expression of Fas/CD44V3 were identified by immunohistochemistry. Results TNF α and its mutants were effectively expressed by tumor cells with dramatic inhibition of tumor growth ( P <0.01). The transmembrane TNF α mutant resulted in the highest tumor regression, up regulated the expression of Fas antigen, induce a striking apoptosis of tumor cells and down regulated the expression of CD44V3 on tumor cells ( P < 0.01 ), while S TNF mutant caused CD4 +/CD8 + lymphocytes infiltration and haemorrhage necrosis of tumor ( P <0.01). Conclusion Direct injection of TM TNF and S TNF nude DNAs could effectively suppress the tumor growth. The mechanisms involved in the tumoricidal activity of the transmembrane TNF α in vivo seems be different from that of secreted TNF α. The former may induce tumor cell apoptosis directely and indirectly via Fas pathway while the latter may exert its antitumor effect by recruiting and activating CD4/CD8 population of lymphocytes. [

关 键 词：跨膜型TNF-Α 分泌型TNF-Α 裸DNA注射 抗瘤效应 Fas 肿瘤免疫 

分 类 号：R730.3[医药卫生—肿瘤] R730.51[医药卫生—临床医学]