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

Abstract: Aims: 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. Main methods: 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. Key findings: 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. Significance: 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. [Copyright &y& Elsevier]