Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Destabilization of TNF-α mRNA by Rapamycin

  • Park, Jong-Woo (Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University) ;
  • Jeon, Ye-Ji (Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University) ;
  • Lee, Jae-Cheol (Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University) ;
  • Ahn, So-Ra (Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University) ;
  • Ha, Shin-Won (Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University) ;
  • Bang, So-Young (Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University) ;
  • Park, Eun-Kyung (Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University) ;
  • Yi, Sang-Ah (Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University) ;
  • Lee, Min-Gyu (Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University) ;
  • Han, Jeung-Whan (Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University)
  • Received : 2011.08.22
  • Accepted : 2011.12.27
  • Published : 2012.01.31
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Abstract

Stimulation of mast cells through the high affinity IgE receptor (Fc${\varepsilon}$RI) 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${\varepsilon}$RI-mediated responses, little is known about the precious mechanism for the expression of tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) in mast cells. Here, we report that rapamycin, a specific inhibitor of mammalian target of rapamycin (mTOR), reduces the expression of TNF-${\alpha}$ in rat basophilic leukemia (RBL-2H3) cells. IgE or specific antigen stimulation of RBL-2H3 cells increases the expression of TNF-${\alpha}$ and activates various signaling molecules including S6K1, Akt and p38 MAPK. Rapamycin specifically inhibits antigeninduced TNF-${\alpha}$ mRNA level, while other kinase inhibitors have no effect on TNF-${\alpha}$ mRNA level. These data indicate that mTOR signaling pathway is the main regulation mechanism for antigen-induced TNF-${\alpha}$ expression. TNF-${\alpha}$ mRNA stability analysis using reporter construct containing TNF-${\alpha}$ adenylate/uridylate-rich elements (AREs) shows that rapamycin destabilizes TNF-${\alpha}$ mRNA via regulating the AU-rich element of TNF-${\alpha}$ mRNA. The antigen-induced activation of S6K1 is inhibited by specific kinase inhibitors including mTOR, PI3K, PKC and $Ca^{2+}$chelator inhibitor, while TNF-${\alpha}$ mRNA level is reduced only by rapamycin treatment. These data suggest that the effects of rapamycin on the expression of TNF-${\alpha}$ 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-${\alpha}$ expression in RBL-2H3 cells.

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References

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