Abstract
ObjectiveN6-isopentenyladenosine (iPA) is an intermediate of the mevalonate pathway that exhibits various anti-cancer effects. However, studies on its anti-inflammatory activity are scarce and underlying molecular mechanisms are unknown. Therefore, we aimed to investigate the ability of iPA to exert anti-inflammatory effects in the human cystic fibrosis (CF) cell model of exacerbated inflammation.Materials and methodsTNFα-stimulated CF cells CuFi-1 and its normal counterpart NuLi-1 were pre-treated with increasing concentrations of iPA and cell viability and proliferation were assessed by MTT and BrdU assays. The effect of iPA on IL-8 and RANTES secretion was determined by ELISA, and the activation and expression of signaling molecules and selenoproteins were studied by Western blot. To assess the direct effect of iPA on NFκB activity, luciferase assay was performed on TNFα-stimulated HEK293/T cells transfected with a NFκB reporter plasmid.ResultsWe demonstrated for the first time that iPA prevents IL-8 and RANTES release in TNFα-stimulated CF cells and this effect is mediated by increasing the expression of the direct NFκB inhibitor IκBα and decreasing the levels of STAT3. Consistent with this, we showed that iPA inhibited TNFα-mediated NFκB activation in HEK/293T cells. Finally, we also found that iPA improved the levels of glutathione peroxidase 1 and thioredoxin reductase 1 only in CF cells suggesting its ability to maintain sufficient expression of these anti-oxidant selenoproteins.ConclusionsOur findings indicate that iPA can exert anti-inflammatory activity especially in the cases of excessive inflammatory response as in CF.
Highlights
N6-isopentenyladenosine is a cytokinin originally identified in plants and present in human cells in a free form or as a modified adenosine bound at position 37 of selenocysteine transfer RNA (Sec-tRNA) [1, 2]
Findings of our study show that iPA inhibits the inflammatory response reducing IL-8 and RANTES production through a mechanism of action involving primarily the downregulation of the nuclear factor-κB (NFκB) and signal transducer and activator of transcription 3 (STAT3) pathways in a cystic fibrosis (CF) cell model characterized by exacerbated inflammation
By treating both CF and non-CF cells with iPA, we found that iPA was highly efficacious in reducing IL-8 and RANTES secretion in both CuFi-1 and NuLi-1 cells but to a different extent. iPA was most efficacious in reducing IL-8 in CuFi-1 cells, whereas a greater decrease of RANTES secretion was observed in tumor necrosis factor α (TNFα)-stimulated NuLi-1 cells
Summary
N6-isopentenyladenosine (iPA) is a cytokinin originally identified in plants and present in human cells in a free form or as a modified adenosine bound at position 37 of selenocysteine transfer RNA (Sec-tRNA) [1, 2]. Only few studies reported that iPA has some immunomodulatory properties being able to selectively expand and directly target natural killer (NK) cells [13] and reduced mouse ear oedema in a murine model of croton oil-induced dermatitis [14].
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