Potential target in allergic responses
Scientists have discovered a new and important role for the inositol-requiring enzyme 1α in immune response.
IRE1α traditionally is known for its role in the unfolded protein response. The UPR helps the endoplasmic reticulum, the main organelle responsible for protein folding, properly respond to the high demands of activated cells. IRE1α, a serine-threonine kinase, is one of the proteins that activate UPR.
In a recent issue of The Journal of Biological Chemistry, scientists at the Northwestern University Feinberg School of Medicine showed that IRE1α also promotes the production of cytokine IL-4, a key regulator in adaptive immunity. Among its effects in the immune system is the stimulation of B cells to produce IgE, an immunoglobulin associated with allergies.
After encountering and recognizing a specific antigen, T lymphocytes proliferate and develop specific effector functions that allow them to respond to particular types of pathogens or control the amplitude of the immune response.
“The strength of T-cell receptor signal, cytokine milieu and the role of co-stimulatory molecules have been analyzed to determine the effect on the development of effector functions,” says Kyeorda Kemp, the first author of the JBC paper. “This study identifies a role for the UPR in promoting T-helper effector functions.”
To better assess the functional roles of IRE1α, Kemp and her team analyzed splenocytes from IRE1α mutant mice and noticed that T cells proliferated normally, but IL-4 production was diminished in activated T cells. This was not caused by abnormalities at the transcriptional level but by reduced IL-4 mRNA instability.
Additionally, a more drastic inhibition of IRE1α by treatment of activated T cells with a potent and specific antagonist further suppressed IL-4 production and inhibited other cytokines associated with a Th2 response, such as IL-13.
“Cytokines IL-4 and IL-13 are associated with the induction of a number of pathologies — most famously allergy and asthma — and inhibiting IRE1α allows for inhibition of these cytokines, making IRE1α an attractive target for the treatment of diseases caused or exacerbated by IL-4 and other Th2 cytokines,” says Kemp. “However, further research will have to be performed to determine if there are any clinical applications for inhibition of IRE1α in Th2 cytokine-mediated pathologies.”