title: Tumor necrosis factor-related apoptosis-inducing ligand induces the expression of proinflammatory cytokines in macrophages and re-educates tumor-associated macrophages to an antitumor phenotype.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising candidate for cancer therapy, because it can induce apoptosis in various tumor cells but not in most normal cells. Although it is well known that TRAIL and its receptors are expressed in many types of normal cells, including immune cells, their immunological effects and regulatory mechanisms are still obscure. In the present study, we demonstrated that TRAIL affected the activity of NF-κB (nuclear factor-κB) and the expression of its downstream proinflammatory cytokines IL-1β (interleukin-1β), IL-6, and tumor necrosis factor α in macrophages. TRAIL also induced microRNA-146a (miR-146a) expression in an NF-κB-dependent manner. As a result, miR-146a was involved as a negative-feedback regulator in the down-regulation of proinflammatory cytokine expression. In addition, the suppression of histone deacetylase (HDAC) activities by trichostatin A improved miR-146a expression due to the up-regulation of the DNA-binding activity of NF-κB at the miR-146a promoter in TRAIL-induced macrophages, suggesting that histone acetylation was involved in the suppression of miR-146a expression. Further investigation revealed that the HDAC subtype HDAC1 directly regulated the expression of miR-146a in TRAIL-stimulated macrophages. Finally, the TRAIL-sensitive human non small cell lung carcinoma cell line NCI-H460 was used to elucidate the physiological significance of TRAIL with respect to tumor-associated macrophages (TAMs). We demonstrated that TRAIL re-educated TAMs to an M1-like phenotype and induced cytotoxic effects in the tumor cells. These data provide new evidence for TRAIL in the immune regulation of macrophages and may shed light on TRAIL-based antitumor therapy in human patients.
authors.affiliation: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Gao
authors.affiliation: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Wang
authors.affiliation: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China.
authors.forename: Yehua
authors.initials: Y
authors.lastname: Ge
authors.affiliation: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China jiangminghong@163.com liuyx2000@yeah.net.
authors.forename: Minghong
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China.
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China.
authors.forename: Dexian
authors.initials: D
authors.lastname: Zheng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D015536:Down-Regulation / Q000187:drug effects; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis; D015850:Interleukin-6 / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016207:Cytokines; D053583:Interleukin-1beta; D015850:Interleukin-6; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D006655:Histone Deacetylases