半乳糖凝集素-1和半乳糖凝集素-3在調控漿狀樹突細胞發育及功能之角色

The Role of Galectin-1 and Galectin-3 in Development and Function of Plasmacytoid Dendritic Cells

呂學翰(Hsueh-Han Lu)

指導教授 ： 朱清良

國立臺灣大學/醫學院/免疫學研究所/碩士(2014年)

https://doi.org/10.6342/NTU.2014.00878

摘要

半乳糖凝集素 (Galectins) 是一種動物性凝集素，可以專一地辨識β-半乳糖 (β-galactosides)。 在免疫系統中，galctin-1 和 -3已經被報導可以調控各種不同的免疫細胞的免疫反應，然而galectin-1和 -3對於漿狀樹突細胞 (plasmacytoid dendritic cell, pDC) 之生長與功能的影響尚未釐清。 pDC在受到病毒感染時，能夠分泌大量的第一型干擾素 (type I Interferon, IFN-I) 並引發各種抗病毒的活性。因此，我們除了研究galectin-1和 -3對於pDC的生長影響外，也用類鐸受體7/9的配體，R848或CpG刺激pDC，以研究pDC產生IFN-I的能力是否會受到galectin-1和 -3的影響。在初步的實驗結果中，我們發現不論是活體外 (in vitro) 或是活體內 (in vivo) 的試驗，皆發現galectin-1和 -3對於pDC的生長沒有顯著的影響。此外，半乳糖凝集素-3基因剔除 (lgals3-/-) pDC在CpG刺激後，其第一型干擾素IFN-I (ifnα, ifnα4, ifnβ)和干擾素調控因子7 (Interferon regulatory factor 7, IRF7) 的基因表現量的增加顯著高於野生型 (wild type, WT) pDC。而且，lgals3-/- pDC在R848或CpG刺激後所產生的IFN-I也比WT pDC來的高。與lgals3-/- pDC相反的是lgals1-/- pDC，在R848或CpG刺激後，其IFN-I 基因表現量的增加顯著低於WT pDC，另外產生的IFN-I 也較WT pDC來的低。因此，我們推測galectin-3 在pDC中可能是扮演了負向調控其產生IFN-I 功能的角色，而galectin-1 則是扮演了正向調控的角色。然而，galectin-1和 -3是經由何種機轉調控IFN-I 的產生，仍然需要進一步的研究。

關鍵字

漿狀樹突細胞 ； 半乳糖凝集素-1 ； 半乳糖凝集素-3 ； 第一型干擾素 ； 類鐸受體7/9

並列摘要

Galectins are animal lectins that can bind to β-galactosides. In the immune system, galectin-1 and galectin-3 have been shown to modulate immune responses in various types of immune cell. However, the role of galectin-1 and galectin-3 in the development and the function of plasmacytoid dendritic cell (pDC) has not yet been studied. pDCs produce type-1-interferon (IFN-I) in response to viral infection and then enhance antiviral activities. Thus, we examined the effect of galectin-1 and galectin-3 on pDC development and IFN-I production by pDCs upon the stimulation of R848 or CpG through TLR7/9. In preliminary results, we show that galectin-1 and galectin-3 didn’t influence the development of pDC in vitro or in vivo. In addition, we found that CpG or R848-induced mRNA levels of IFN-I (ifnα, ifnα4, ifnβ) and interferon regulatory factor (IRF7) were significantly higher in gal-3-/- Flt3L-BMDCs and in the contrast, significantly lower in gal-1-/- Flt3L-BMDCs when compared to that in WT Flt3L-BMDCs. Moreover, at the protein level, the production of IFNα by gal-3-/- Flt3L-BMDCs stimulated with CpG or R848 is higher than WT Flt3L-BMDCs. And, the production of IFNα by gal-3-/- Flt3L-BMDCs is lower than WT Flt3L-BMDCs. Our data suggested that galectin-3 may negatively regulate the function of pDCs, on the other hand that galectin-1 may positively regulate the function of pDC. However, the mechanism of how galectin-3 and galectin-1 involved in IFN-I production need to be further explored.

並列關鍵字

plasmacytoid dendritic cell ； galectin-1 ； galectin-3 ； type-I-IFN ； TLR7/9

參考文獻

Arroyo, D. S., Gaviglio, E. A., Peralta Ramos, J. M., Bussi, C., Rodriguez-Galan, M. C., & Iribarren, P. (2014). Autophagy in inflammation, infection, neurodegeneration and cancer. Int Immunopharmacol, 18(1), 55-65. doi: 10.1016/j.intimp.2013.11.001

Bernardes, E. S., Silva, N. M., Ruas, L. P., Mineo, J. R., Loyola, A. M., Hsu, D. K., . . . Roque-Barreira, M. C. (2006). Toxoplasma gondii infection reveals a novel regulatory role for galectin-3 in the interface of innate and adaptive immunity. Am J Pathol, 168(6), 1910-1920. doi: 10.2353/ajpath.2006.050636

Bjorck, P., Leong, H. X., & Engleman, E. G. (2011). Plasmacytoid dendritic cell dichotomy: identification of IFN-alpha producing cells as a phenotypically and functionally distinct subset. J Immunol, 186(3), 1477-1485. doi: 10.4049/jimmunol.1000454

Blanco, P., Palucka, A. K., Gill, M., Pascual, V., & Banchereau, J. (2001). Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus. Science, 294(5546), 1540-1543. doi: 10.1126/science.1064890

Blasius, A. L., Cella, M., Maldonado, J., Takai, T., & Colonna, M. (2006). Siglec-H is an IPC-specific receptor that modulates type I IFN secretion through DAP12. Blood, 107(6), 2474-2476. doi: 10.1182/blood-2005-09-3746