Inhibition of Pim1 kinase prevents peanut allergy by enhancing Runx3 expression and suppressing T_H2 and T_H17 T-cell differentiation

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• 作者：Meiqin Wang ; Masakazu Okamoto ; Joanne Domenico ; Junyan Han ; Shigeru Ashino ; Yoo Seob Shin ; Erwin W. Gelf
• 关键词：Pim1 kinase ; Runx3 ; peanut ; intestinal allergy ; TH2 ; TH17
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2012
• 出版时间：October, 2012
• 年：2012
• 卷：130
• 期：4
• 页码：932-944.e12
• 全文大小：4938 K

文摘

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Background

The provirus integration site for Moloney murine leukemia virus (Pim) 1 kinase is an oncogenic serine/threonine kinase implicated in cytokine-induced cell signaling, whereas Runt-related transcription factor (Runx) has been implicated in the regulation of T-cell differentiation. The interaction of Pim1 kinase and Runx3 in the pathogenesis of peanut allergy has not been defined.

Objectives

We sought to determine the effects of Pim1 kinase modulation on Runx3 expression and T_H2 and T_H17 cell function in an experimental model of peanut allergy.

Methods

A Pim1 kinase inhibitor was administered to peanut-sensitized and challenged wild-type and Runx3^+/? mice. Symptoms, intestinal inflammation, and Pim1 kinase and Runx3 mRNA expression and protein levels were assessed. The effects of Pim1 kinase inhibition on T_H1, T_H2, and T_H17 differentiation in?vivo and in?vitro were also determined.

Results

Peanut sensitization and challenge resulted in accumulation of inflammatory cells and goblet cell metaplasia and increased levels of Pim1 kinase and T_H2 and T_H17 cytokine production but decreased levels of Runx3 mRNA and protein in the small intestines of wild-type mice. All of these findings were normalized with Pim1 kinase inhibition. In sensitized and challenged Runx3^+/? mice, inhibition of Pim1 kinase had less effect on the development of the full spectrum of intestinal allergic responses. In?vitro inhibition of Pim1 kinase attenuated T_H2 and T_H17 cell differentiation and expansion while maintaining Runx3 expression in T-cell cultures from wild-type?mice; these effects were reduced in T-cell cultures from Runx3^+/? mice.

Conclusion

These data support a novel regulatory axis involving Pim1 kinase and Runx3 in the control of food-induced allergic reactions through the regulation of T_H2 and T_H17 differentiation.