KMID : 0606920120200010043
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Biomolecules & Therapeutics 2012 Volume.20 No. 1 p.43 ~ p.49
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Destabilization of TNF-¥á mRNA by Rapamycin
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Park Jong-Won
Jeon Ye-Ji Lee Jae-Cheol Ahn So-Ra Ha Shin-Won Bang So-Young Park Eun-Kyung Yi Sang-Ah Lee Min-Gyu Han Jeung-Whan
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Abstract
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Stimulation of mast cells through the high affinity IgE receptor (Fc¥åRI) induces degranulation, lipid mediator release, and cytokine secretion leading to allergic reactions. Although various signaling pathways have been characterized to be involved in the Fc¥åRI-mediated responses, little is known about the precious mechanism for the expression of tumor necrosis factor-¥á (TNF-¥á) in mast cells. Here, we report that rapamycin, a specific inhibitor of mammalian target of rapamycin (mTOR), reduces the expression of TNF-¥á in rat basophilic leukemia (RBL-2H3) cells. IgE or specific antigen stimulation of RBL-2H3 cells increases the expression of TNF-¥á and activates various signaling molecules including S6K1, Akt and p38 MAPK. Rapamycin specifically inhibits antigen-induced TNF-¥á mRNA level, while other kinase inhibitors have no effect on TNF-¥á mRNA level. These data indicate that mTOR signaling pathway is the main regulation mechanism for antigen-induced TNF-¥á expression. TNF-¥á mRNA stability analysis using reporter construct containing TNF-¥á adenylate/uridylate-rich elements (AREs) shows that rapamycin destabilizes TNF-¥á mRNA via regulating the AU-rich element of TNF-¥á mRNA. The antigen-induced activation of S6K1 is inhibited by specific kinase inhibitors including mTOR, PI3K, PKC and Ca2+chelator inhibitor, while TNF-¥á mRNA level is reduced only by rapamycin treatment. These data suggest that the effects of rapamycin on the expression of TNF-¥á mRNA are not mediated by S6K1 but regulated by mTOR. Taken together, our results reveal that mTOR signaling pathway is a novel regulation mechanism for antigen-induced TNF-¥á expression in RBL-2H3 cells.
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KEYWORD
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Mast cells, S6K1, Rapamycin, mTOR, mRNA, Stability
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