Arachidonic acid and its COX1/2 metabolites inhibit interferon-γ mediated induction of indoleamine-2,3 dioxygenase in THP-1 cells and human monocytes

Abstract

Using human acute monocytic leukaemic THP-1 cells and human primary monocytes, this study examined the ability of arachidonic acid (AA) to modulate the activity of the IFNγ signalling cascade and its downstream effector indoleamine 2,3-dioxygenase (IDO). We established that AA inhibited IDO enzyme activity with an IC(50) of 20 μM in THP-1 cells and 12 μM in monocytes, and this was due to reduced expression of INDO1 mRNA and reduced level of IDO protein. Further mechanistic analysis revealed that AA interfered with the transcriptional function of the IFNγ signalling pathway by reducing phosphorylation of signal transducer and activator of transcription (STAT1) on tyrosine 701. The importance of AA metabolism via the COX and LOX pathways was investigated using inhibitors. Indomethacin, but not nordihydroguaiaretic acid, prevented the AA-mediated inhibition of STAT1 phosphorylation and thereby IDO enzymatic activity in THP-1 cells and monocytes. This is the first study to demonstrate that AA inhibits the IFNγ/STAT/IDO pathway, and this function is mediated by COX1/2 produced metabolites of AA. We now have evidence demonstrating that the AA metabolites, prostaglandins A(2) and D(2,) were highly inhibitory towards the IFNγ pathway, while prostaglandin E(2) had no effect. Together, these results indicate that the fatty acid AA has the potential to modulate the immunosuppressive activity of IDO and may form the basis of novel inhibitory compounds.