title: Inhibition of Pim1 kinase prevents peanut allergy by enhancing Runx3 expression and suppressing T(H)2 and T(H)17 T-cell differentiation.
abstract: 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.
  
  
  OBJECTIVE
  We sought to determine the effects of Pim1 kinase modulation on Runx3 expression and T(H)2 and T(H)17 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(H)1, T(H)2, and T(H)17 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(H)2 and T(H)17 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(H)2 and T(H)17 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.
  
  
  CONCLUSIONS
  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(H)2 and T(H)17 differentiation.
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO 80206, USA.
authors.forename: Meiqin
authors.initials: M
authors.lastname: Wang
authors.forename: Masakazu
authors.initials: M
authors.lastname: Okamoto
authors.forename: Joanne
authors.initials: J
authors.lastname: Domenico
authors.forename: Junyan
authors.initials: J
authors.lastname: Han
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ashino
authors.forename: Yoo Seob
authors.initials: YS
authors.lastname: Shin
authors.forename: Erwin W
authors.initials: EW
authors.lastname: Gelfand
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D018793:Interleukin-13 / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D007583:Jejunum / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D021183:Peanut Hypersensitivity / Q000276:immunology / Q000517:prevention & control*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D058504:Th17 Cells / Q000166:cytology*; D018418:Th2 Cells / Q000166:cytology*
chemical_list: D050677:Core Binding Factor Alpha 3 Subunit; D018793:Interleukin-13; D020381:Interleukin-17; D012333:RNA, Messenger; C493730:Runx3 protein, mouse; C496636:Pim1 protein, mouse; D051573:Proto-Oncogene Proteins c-pim-1