Novel 1-alkyl-tryptophan derivatives downregulate IDO1 and IDO2 mRNA expression induced by interferon-gamma in dendritic cells.
Indoleamine 2,3-dioxygenase (IDO) is an enzyme that suppresses adaptive T-cell immunity by catabolizing tryptophan from the cellular microenvironment. Inhibition of IDO pathway might enhance the efficacy of immunotherapeutic strategies for cancer. We synthesized 1-alkyl-tryptophan targeted IDO inhibitors and compared their effects on IDO expression and activity in dendritic cells (DCs) with the common IDO inhibitor 1-methyl-DL-tryptophan (1-MT). The IDO gene expression was examined by RT-PCR and realtime PCR. The toxicity of these analogs on the proliferation of DCs was detected by MTT assay. All of these analogs inhibited IDO expression and activity induced by IFN-gamma and showed no cytotoxicity to DCs at 100 microM. 1-MT intensively suppressed IDO1 expression and activity in DCs, and 1-propyl-tryptophan (1-PT) and 1-isopropyl-tryptophan (1-isoPT) moderately inhibited them. 1-Butyl-tryptophan (1-BT) and 1-ethyl-tryptophan (1-ET) mainly inhibited IDO2 expression. Our results suggest that those analogs differed in their inhibitory activity on IDO expression may give us a clue for developing active IDO inhibitors.
Sun
Ting
T
Department of Cardiac Function, Shanghai Ninth People's Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, China. beibeisun2008@163.com
Chen
Xiang-Hua
XH
Tang
Zheng-De
ZD
Cai
Jiong
J
Wang
Xiao-Yan
XY
Wang
Shih-Chen
SC
Li
Zhao-Long
ZL
D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000201:enzymology; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics* / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics*; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D012333:RNA, Messenger; D011994:Recombinant Proteins; D007371:Interferon-gamma