Treatment of established TH2 cells with 4?8c, an inhibitor of IRE1?, blocks IL-5 but not IL-4 secretion.

ABSTRACT:

Background

T cell activation induces ER stress and upregulates Inositol Requiring Enzyme 1 alpha (IRE1?), an activator of the unfolded protein response (UPR) pathway. Inhibition of IRE1? RNase activity in activated CD4⁺ splenocytes from naïve mice, via treatment of the cells with the commercially available drug 4?8c upon activation, results in the reduction of the secretion of proteins IL-5, IL-4, and IL-13. Prior to this work, it was unknown if 4?8c could inhibit TH2 cytokines in established TH2 cells, cells that are crucial in promoting disease in severe asthma.

Results

Treatment of a mouse T helper (TH)2 cell line and differentiated human TH2 cells with 4?8c 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.

Conclusion

These data suggest that the inhibition of IL-5 was due to post-translational processes. IL-5 promotes chronic, inflammatory asthma, and 4?8c blocks its expression in T cells in vitro. Future studies will determine if 4?8c treatment can ameliorate the effects of the cytokine IL-5 in a disease model.

SUBMITTER: Poe C 

PROVIDER: S-EPMC6327572 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature