Oxidative stress stimulates IL‐4 and IL‐6 production in mast cells by an APE/Ref‐1‐dependent pathway

Mast cells are exposed to an oxidative environment in the course of allergic and inflammatory reactions. We have examined the effects of H2O2 stimulation in a primary rat basophilic leukemia cell line (RBL‐2H3) and compared with IgE‐dependent stimulation. Like IgE stimulation, H2O2 up‐regulates IL‐4 and IL‐6 gene expression and cytokine secretion, shows a little effect on IL‐5 but does not induce IL‐10 gene expression. Simultaneous H2O2 treatment and FcϵRI triggering of mast cells has additive effects on IL‐4 expression. In addition, we show that both stimuli induce the nuclear translocation of APE/Ref‐1, a bifunctional enzyme that stimulates the DNA‐binding activity of several transcription factors through the reduction of highly reactive cysteines. Conditional inactivation of APE/Ref‐1 expression abolishes H2O2‐induced IL‐4 and IL‐6 gene expression but does not affect that induced by FcϵRI stimulation. Our findings indicate that oxidative stress activates the gene expression of a specific cytokine pattern in mast cells through an APE/Ref‐1‐dependent pathway, which is distinct from theone that is activated by FcϵRI stimulation. Nonetheless, H2O2 and FcϵRI signalings are additive in augmenting IL‐4 production. Most importantly, oxidative stress can induce a pro‐type 2 inflammatory response from mast cells that is independent of FcϵRI stimulation.