This study examines ABC-transporters as a potential therapeutic target in dendritic cell (DC) modulation under hypoxia and LPS. Functional capacity of DCs (mixed lymphocyte reaction, MLR) and maturation of iDCs was evaluated in the presence or absence of specific ABC-transporter inhibitors.

Monocytes-derived DCs were cultured in the presence of IL-4/GM-CSF. Their maturation under hypoxia or LPS conditions was evaluated by assessing the expression of maturation phenotypes by flow cytometry. The effect of ABC transporters on DC maturation was determined using specific inhibitors for MDR1 and MRPs. The functional capacity of DCs depending on their maturation status to elicit T-cell alloresponse was studied by MLR.

Mature-DCs showed higher P-glycoprotein (Pgp) expression by confocal microscopy. An up-regulation of maturation markers was observed in hypoxia and LPS-DC, defining two different DC sub-population profiles, plasmacytoid versus conventional-like respectively and different cytokine release TH2 versus TH1 depending on the stimuli. HIF-1Α protein expression on hypoxia DCs significantly increased and ABC inhibitors did not modified it. Hypoxia-DCs induced more B-lymphocyte proliferation than control-iDC (56% vs 9%) meanwhile LPS-DCs induced more CD8-lymphocyte proliferation (67% vs 16%). ABC-transporter-inhibitors strongly abrogated DC maturation, induced significantly less lymphocyte proliferation and reduced cytokine release compared with stimulated-DCs without inhibitors.

We conclude that diverse stimuli, hypoxia or LPS induce different profile in the maturation and functionality of DC. Pgp appers to play a role in DCs events. Thus, ABC-transporters emerge as a potential targets in immunosuppressive therapies interfering with DCs maturation, thereby abrogating innate immune response when it is activated after ischemia.

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