Treatment of established TH2 cells with 4μ8c, an inhibitor of IRE1α, blocks IL-5 but not IL-4 secretion

T cell activation induces ER stress and upregulates Inositol Requiring Enzyme 1 alpha (IRE1α), an activator of the unfolded protein response (UPR) pathway. Inhibition of IRE1α RNase activity in activated CD4+ splenocytes from naïve mice, via treatment of the cells with the commercially available drug 4μ8c upon activation,

These data suggest that the inhibition of IL-5 was due to post-translational processes. IL-5 promotes chronic, inflammatory asthma, and 4μ8c blocks its expression in T cells in vitro. Future studies will determine if 4μ8c treatment can ameliorate the effects of the cytokine IL-5 in a disease model.

Treatment of a mouse T helper (TH)2 cell line and differentiated human TH2 cells with 4μ8c resulted in inhibition of IL-5, but not IL-4, as measured by ELISA. The reduced cytokine expression was not due to differences in mRNA stability or mRNA levels; it appears to be due to a defect in secretion, as the cells produce cytokines IL-5 as measured by flow cytometry and western blot.