The Serine-threonine Kinase Inositol-requiring Enzyme 1α (IRE1α) Promotes IL-4 Production in T Helper Cells

Background: IRE1 is a kinase important for the misfolded protein response. Results: IRE1 promotes IL-4 production by stabilizing IL-4 mRNA, and IRE1-specific inhibitor 48C suppresses IL-4 production. Conclusion: IRE1 is a positive regulator of IL-4 production by T helper cells. Significance: Cytokine IL-4 has been implicated in allergic response. Our discovery that IRE1 promotes IL-4 production implies that IRE1 inhibition has a therapeutic potential in allergic disease treatment. The inositol-requiring enzyme 1 (IRE1) is a serine-threonine kinase that plays crucial roles in activating the unfolded protein response. Studies suggest that IRE1 is activated during thymic T cell development and in effector CD8(+) T cells. However, its role in regulating T helper cell differentiation remains unknown. We find that IRE1 is up-regulated and activated upon CD4(+) T cell activation and plays an important role in promoting cytokine IL-4 production. CD4(+) T cells from IRE1 KO mice have reduced IL-4 protein expression, and this impaired IL-4 production is not due to the altered expression of Th2 lineage-specific transcription factors, such as GATA3. Instead, IL-4 mRNA stability is reduced in IRE1 KO T cells. Furthermore, treatment of T cells with an IRE1-specific inhibitor, 48C, leads to a block in IL-4, IL-5, and IL-13 production, confirming the role of IRE1 in the regulation of IL-4. This study identifies a regulatory function for IRE1 in the promotion of IL-4 in T cells.