title: MEK/Erk-based negative feedback mechanism involved in control of Steel Factor-triggered production of Krüppel-like factor 2 in mast cells.
abstract: The receptor tyrosine kinase, c-kit (Steel Factor (SF) receptor) controls survival, proliferation, chemotaxis, and secretion of proinflammatory cytokines in mast cells (MCs). Activation of c-kit results, amongst others, in induction of the PI3K and MEK/Erk pathways. Comparison of two MEK inhibitors, the specific, widely used U0126 and the more selective PD0325901, in different MC models revealed severe differences on SF-induced expression of proinflammatory cytokines IL-6 and TNF-α as well as the transcription factor Krüppel-like factor 2 (KLF2). Expression of the latter in MCs was not investigated so far. Whereas SF-induced expression of IL-6, TNF-α, and KLF2 was unaltered by U0126, it was significantly augmented by PD0325901. The effect of PD0325901 was corroborated by a second selective MEK inhibitor, PD184352 (Cl-1040), indicating the presence of MEK/Erk-based negative feedback mechanism(s) downstream of c-kit activation. Further analysis of KLF2 production revealed a positive function of PI3K. Depending on additional stimuli (e.g. antigen, IGF-1, LPS, thapsigargin), SF-triggered KLF2 expression was differentially modified, most likely controlled by the respective ratio between MEK/Erk and PI3K pathway activation. Moreover, the statin, simvastatin, was demonstrated to upregulate expression of KLF2 in MCs. In conclusion, data obtained by solely using the MEK inhibitor U0126 have to be carefully corroborated by using more selective inhibitors, such as PD0325901 or PD184352. SF-induced expression of the transcription factor KLF2 and its regulation by the MEK/Erk and PI3K pathways could impact on physiological as well as pathophysiological MC functions.
authors.affiliation: RWTH Aachen University, Medical Faculty, Department of Biochemistry and Molecular Immunology, Institute of Biochemistry and Molecular Biology, D-52074 Aachen, Germany.
authors.forename: J S
authors.initials: JS
authors.lastname: Marschall
authors.forename: T
authors.initials: T
authors.lastname: Wilhelm
authors.forename: W
authors.initials: W
authors.lastname: Schuh
authors.forename: M
authors.initials: M
authors.lastname: Huber
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008407:Mast Cells; D051379:Mice; D009570:Nitriles / Q000494:pharmacology; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000235:genetics*; D019821:Simvastatin / Q000494:pharmacology; D019089:Stem Cell Factor / Q000235:genetics / Q000378:metabolism*; D019284:Thapsigargin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D001549:Benzamides; D002070:Butadienes; D000960:Hypolipidemic Agents; D015850:Interleukin-6; C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D008070:Lipopolysaccharides; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D019089:Stem Cell Factor; D014409:Tumor Necrosis Factor-alpha; C113580:U 0126; D019284:Thapsigargin; D007334:Insulin-Like Growth Factor I; C506614:mirdametinib; D004159:Diphenylamine; D019821:Simvastatin; D058539:Phosphatidylinositol 3-Kinase; D020930:MAP Kinase Kinase Kinases