title: Mitogen-activated protein kinase kinase 1/extracellular signal-regulated kinase (MEK-1/ERK) inhibitors sensitize reduced glucocorticoid response mediated by TNFalpha in human epidermal keratinocytes (HaCaT).
abstract: Glucocorticoids (GCs) are essential drugs administered topically or systematically for the treatment of autoimmune skin diseases such as pemphigus. However, a certain proportion of patients does not respond well to GCs. Although studies on the relationship between cytokines and GC insensitivity in local tissues have attracted attention recently, little is known about the underlying mechanism(s) for GC insensitivity in epidermal keratinocytes. Here, we report that tumor necrosis factor (TNF) alpha reduces GC-induced transactivation of endogenous genes as well as a reporter plasmid which contains GC responsive element (GRE) in human epidermal keratinocyte cells (HaCaT). The GC insensitivity by TNFalpha was not accompanied by changes in mRNA expressions of GR isoforms (alpha or beta). However, we observed that mitogen-activated protein kinase kinase-1/extracellular signal-regulated kinase (MEK-1/ERK) inhibitors (PD98059 and U0126) significantly sensitized the GC-induced transactivation of anti-inflammatory genes (glucocorticoid-induced leucine zipper (GILZ) and mitogen-activated protein kinase phosphatase (MKP)-1) and FK506 binding protein (FKBP) 51 gene in the presence of TNFalpha. Additionally, we observed that TNFalpha reduced prednisolone (PSL)-dependent nuclear translocation of GR, which was restored by pre-treatment of MEK-1 inhibitors. This is the first study demonstrating a role of the MEK-1/ERK cascade in TNFalpha-mediated GC insensitivity. Our data suggest that overexpression of TNFalpha leads to topical GC insensitivity by reducing GR nuclear translocation in keratinocytes, and our findings also suggest that inhibiting the MEK-1/ERK cascade may offer a therapeutic potential for increasing GC efficacy in epidermis where sufficient inflammatory suppression is required.
authors.affiliation: Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. knjond@ps.toyaku.ac.jp
authors.forename: Kenji
authors.initials: K
authors.lastname: Onda
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nagashima
authors.forename: Yo
authors.initials: Y
authors.lastname: Kawakubo
authors.forename: Shota
authors.initials: S
authors.lastname: Inoue
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Hirano
authors.forename: Kitaro
authors.initials: K
authors.lastname: Oka
mesh_terms: D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D005938:Glucocorticoids / Q000008:administration & dosage*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1