1-Methyl-tryptophan can interfere with TLR signaling in dendritic cells independently of IDO activity.
The compound 1-methyl-tryptophan (1-MT) is a competitive inhibitor of IDO that can break tolerance and induce fetus, graft, and tumor rejection. Because of its broad effect on immune-related mechanisms, the direct action of 1-MT on human monocyte-derived dendritic cells (DC) was analyzed. It is shown here that the effect of 1-MT on DC is dependent on the maturation pathway. Although 1-MT had no effect on DC stimulated by the TLR3 ligand poly(I:C), it strongly enhanced the Th1 profile of DC stimulated with TLR2/1 or TLR2/6 ligands. Drastic changes in the function of DC stimulated by the TLR4 ligand LPS were induced by 1-MT. These cells could still activate allogeneic and syngeneic T cells but stimulation yielded T cells secreting IL-5 and IL-13 rather than IFN-gamma. This action of 1-MT correlated with an increased phosphorylation of p38 and ERK MAPKs and sustained activation of the transcription factor c-Fos. Inhibiting p38 and ERK phosphorylation with synthetic inhibitors blocked the effect of 1-MT on LPS-stimulated DC. Thus, 1-MT can modulate DC function depending on the maturation signal and independently of its action on IDO. This is consistent with previous observations and will help further understanding the mechanisms of DC polarization.
Agaugué
Sophie
S
Institut National de la Santé et de la Recherche Médicale Unité 503, Institut Fédératif de Recherche 128 BioSciences Lyon-Gerland, Université Claude Bernard Lyon I, 21 Avenue Tony Garnier, F-69365 Lyon, France.
Perrin-Cocon
Laure
L
Coutant
Frédéric
F
André
Patrice
P
Lotteau
Vincent
V
D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors* / Q000502:physiology*; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000494:pharmacology
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D051193:Toll-Like Receptors; D014364:Tryptophan