title: Identification of the signaling pathway of TNF-α-induced CCL17/TARC transcription in a canine keratinocyte cell line.
abstract: A CC chemokine, CCL17/TARC, has been shown to be a factor in the immunopathogenesis of canine atopic dermatitis (cAD). In canine keratinocytes, the transcription of CCL17 mRNA is preferentially induced by tumor necrosis factor-alpha (TNF-α); however, its regulatory mechanism has not been elucidated. The aim of the present study is to clarify the regulatory mechanism of TNF-α-induced CCL17 mRNA transcription in canine keratinocytes leading to the development of a chemokine-targeted therapy for cAD. In a cell line of canine epidermal keratinocyte, CPEK, stimulation with TNF-α induced not only the activation of nuclear factor-kappa B (NF-κB) but also the phosphorylation of c-Jun-N-terminal kinase (JNK) and mitogen-activated protein kinase p38 (p38). Extracellular signal-regulated kinase (ERK) was found to be constitutively phosphorylated, which was temporarily augmented by TNF-α. Results of the inhibition assay indicated that the CCL17 mRNA transcription level was significantly decreased by p38 inhibitors but was not altered by either JNK or NF-κB inhibitors. Surprisingly, the ERK inhibitor increased the transcription level of CCL17 mRNA. Stimulation with epidermal growth factor (EGF), an ERK activator, suppressed the transcription of CCL17 mRNA. The present results suggest that TNF-α-induced CCL17 mRNA transcription in CPEK is positively regulated by p38 but negatively controlled by ERK.
authors.affiliation: The United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Sanae
authors.initials: S
authors.lastname: Shibata
authors.forename: Sadatoshi
authors.initials: S
authors.lastname: Maeda
authors.forename: Naho
authors.initials: N
authors.lastname: Kondo
authors.forename: Naoki
authors.initials: N
authors.lastname: Chimura
authors.forename: Akiko
authors.initials: A
authors.lastname: Inoue
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Fukata
mesh_terms: D000818:Animals; D002460:Cell Line; D054414:Chemokine CCL17 / Q000235:genetics / Q000378:metabolism*; D004285:Dogs; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism*; D008156:Luciferases; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D054414:Chemokine CCL17; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D008156:Luciferases; D020929:Mitogen-Activated Protein Kinase Kinases