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The immunostimulatory effects and pro-apoptotic activity of rhCNB against Lewis lung cancer is mediated by Toll-like receptor 4
Yang, Jinju1,2; Zhang, Hongwei1; Zhu, Ziwei1; Gao, Yadan1; Xiang, Benqiong1; Wei, Qun1
2019-08-01
Source PublicationCANCER MEDICINE
ISSN2045-7634
Volume8Issue:9Pages:4441-4453
AbstractBackground Recombinant human calcineurin B subunit (rhCNB) has been shown to be an immune-stimulatory protein promoting cytokine production and inducing phenotypic maturation of Dendritic cells (DCs). In vivo, it has good antitumor efficacy, and has potential as an antitumor drug. Exogenous rhCNB was found to be internalized into tumor cells via the Toll-like receptor 4 (TLR4) complex, but it was not known whether its immuno-modulatory and antitumor functions involved entry by this same route. Methods The production and secretion of the cytokines and chemokines in innate immune cells induced by rhCNB were determined by ELISA, and the expression of CD40, CD80, CD86, and MHCII was analyzed by FACs. Experimental Lewis lung cancer (LLC) model was prepared in C57 BL/6 wild-type (WT) mice, TLR4(-/-) mice or their littermates by the inoculation of LLCs in their right armpit, and then administrated daily intraperitoneal injections (0.2 mL) of normal saline, rhCNB 20 mg/kg, and rhCNB 40 mg/kg, respectively. Results Recombinant human calcineurin B subunit promoted the production of antitumor cytokines by innate immune cells, and culture supernatants of rhCNB-stimulated immune cells induced apoptosis of LLCs. In addition, rhCNB up-regulated CD40, CD80, CD86, and MHCII expression in macrophages and DCs in TLR4(+) cells but failed to do so in TLR4 deficient cells. rhCNB also induced the formation of CD4(+) and CD8(+)T cells in splenocytes from WT mice, but not from TLR4-deficient littermates. Intraperitoneal administration of WT C57BL/6 mice with rhCNB resulted in a 50% reduction in LLC tumor growth, but failed to inhibit tumor growth in TLR4(-/-) littermates. Conclusions The in vivo antitumor and immunomodulatory effects of rhCNB are mediated by the TLR4. This conclusion is important for the further understanding and development of rhCNB as an antitumor drug.
Keywordantitumor drug antitumor immunity innate immunity rhCNB Toll-like receptor 4
DOI10.1002/cam4.2158
Language英语
WOS KeywordCALCINEURIN B-SUBUNIT ; INNATE IMMUNITY ; TUMOR-CELLS ; AGONISTS ; PROTEIN ; RECOGNITION ; ENDOCYTOSIS ; ACTIVATION ; EXPRESSION ; LIGAND
Funding ProjectNational Natural Science Foundation of China ; National Important Basic Research Project ; National Important Novel Medicine Research Project
WOS Research AreaOncology
WOS SubjectOncology
Funding OrganizationNational Natural Science Foundation of China ; National Important Basic Research Project ; National Important Novel Medicine Research Project
WOS IDWOS:000478606700034
PublisherWILEY
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Document Type期刊论文
Identifierhttp://ir.ipe.ac.cn/handle/122111/30323
Collection中国科学院过程工程研究所
Corresponding AuthorXiang, Benqiong; Wei, Qun
Affiliation1.Beijing Normal Univ, Gene Engn & Biotechnol Beijing Key Lab, Dept Biochem & Mol Biol, Beijing, Peoples R China
2.Chinese Acad Sci, Inst Proc Engn, Natl Key Lab Biochem Engn, Beijing, Peoples R China
Recommended Citation
GB/T 7714
Yang, Jinju,Zhang, Hongwei,Zhu, Ziwei,et al. The immunostimulatory effects and pro-apoptotic activity of rhCNB against Lewis lung cancer is mediated by Toll-like receptor 4[J]. CANCER MEDICINE,2019,8(9):4441-4453.
APA Yang, Jinju,Zhang, Hongwei,Zhu, Ziwei,Gao, Yadan,Xiang, Benqiong,&Wei, Qun.(2019).The immunostimulatory effects and pro-apoptotic activity of rhCNB against Lewis lung cancer is mediated by Toll-like receptor 4.CANCER MEDICINE,8(9),4441-4453.
MLA Yang, Jinju,et al."The immunostimulatory effects and pro-apoptotic activity of rhCNB against Lewis lung cancer is mediated by Toll-like receptor 4".CANCER MEDICINE 8.9(2019):4441-4453.
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