Synthetic isoforms of endogenous sulfatides differently modulate indoleamine 2,3-dioxygenase in antigen presenting...

To investigate whether sulfatides modulate indoleamine 2,3-dioxygenase (IDO)1, a fine-tuned enzymatic mechanism for controlling immune responses, gene expression/function in antigen presenting cells (APC). The relationship between structure and activity (SAR) of newly synthesized sulfatide isoforms (C16:0, C18:0, C22:0, C24:1) was also evaluated.

CD1d-transfected THP-1 human cells were used as APC and treated with increasing concentrations (0.01-10μΜ) of each compound for an appropriate period of time. The gene expression and the enzymatic activity of IDO1 were examined using reverse transcription-polymerase chain reaction (RT-PCR) and high performance liquid chromatography (HPLC). Compound-untreated cells were taken as negative, while 1000U/ml interferon (IFN)-γ-treated cells as positive controls.

Not all sulfatides induced the same effect: the basal IDO1 expression was significantly reduced (-48 ± 3% at 0.01μΜ) by C16:0 sulfatide, while it was increased by C18:0 or C24:1 sulfatide (+87 ± 7% and +50 ± 5% at 1μΜ, respectively) over negative controls; C22:0 sulfatide resulted ineffective at all concentrations tested. These effects functionally correlated with changes in IDO1 activity: l-kynurenine contents in the culture media were significantly reduced by C16:0 sulfatide (-29 ± 4% at 0.01μM), while it was increased by C18:0 or C24:1 sulfatide (+61 ± 8% and +48 ± 4% at 1μM, respectively) over negative controls. C22:0 sulfatide resulted ineffective at all concentration tested.

The overall data demonstrate that specific sulfatide isoforms differently modulate IDO1 in APC. The sulfatide-induced effects are structurally dependent on the length/saturation of their fatty acid chain.