3, 5, 3′-Triiodothyroacetic acid (TRIAC) is an anti-inflammatory drug that targets toll-like receptor 2
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Drug repositioning is a strategy that explores new pharmaceutical applications of previously launched or failed drugs, and is advantageous since it saves capital and time. In this study, we examined the inhibition of TLR2 signaling by drug candidates. HEK-Blue™-hTLR2 cells were pretreated with drugs and stimulated using the TLR2 ligand, Pam3CSK4. Among the drugs that inhibited TLR2 signaling, we selected TRIAC, which is yet to be patented. Pretreatment with TRIAC decreased the TLR2 level and the phosphorylation of Akt and MAPKs in HEK-Blue™-hTLR2 cells. Since TLR2 is overexpressed in patients with acute hepatitis, we confirmed that TRIAC alleviates necrosis in a mouse model of Con A-induced acute hepatitis. The serum AST and ALT levels are indicators of liver damage, and are increased in Con A-induced hepatitis. Additionally, TLR2 and inflammatory cytokine levels are increased following administration of Con A and lead to liver damage. TRIAC decreased the serum levels of AST and ALT, and reduced liver tissue necrosis in mice with Con A-induced acute fulminant liver damage, by reducing the levels of inflammatory cytokines. In conclusion, TRIAC alleviates inflammation in mouse models of Con A-induced hepatitis by inhibiting the phosphorylation of Akt and MAPKs, the sub-mechanisms underlying TLR2 signaling.
KeywordsTRIAC TLR2 Acute hepatitis Akt MAPK
This research was supported by Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Science, ICT & Future Planning (Grant Numbers NRF-2013M3A9B6075890, NRF-2015M3A9C7030121).
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Conflict of interest
The authors declare no potential conflict of interest with respect to the authorship and/or publication of this article.
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