Reference - Detail
|Author||Mizuno K, Fukami T, Toyoda Y, Nakajima M, Yokoi T.|
|Title||Terbinafine stimulates the pro-inflammatory responses in human monocytic THP-1 cells through an ERK signaling pathway.|
AIMS:Oral antifungal terbinafine has been reported to cause liver injury with inflammatory responses in a small percentage of patients. However the underlying mechanism remains unknown. To examine the inflammatory reactions, we investigated whether terbinafine and other antifungal drugs increase the release of pro-inflammatory cytokines using human monocytic cells.
MAIN METHODS:Dose- and time-dependent changes in the mRNA expression levels and the release of interleukin (IL)-8 and tumor necrosis factor (TNF)α from human monocytic THP-1 and HL-60 cells with antifungal drugs were measured. Effects of terbinafine on the phosphorylation of extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein (MAP) kinase and c-Jun N-terminal kinase (JNK)1/2 were investigated.
KEY FINDINGS:The release of IL-8 and TNFα from THP-1 and HL-60 cells was significantly increased by treatment with terbinafine but not by fluconazole, suggesting that terbinafine can stimulate monocytes and increase the pro-inflammatory cytokine release. Terbinafine also significantly increased the phosphorylation of ERK1/2 and p38 MAP kinase in THP-1 cells. Pretreatment with a MAP kinase/ERK kinase (MEK)1/2 inhibitor U0126 significantly suppressed the increase of IL-8 and TNFα levels by terbinafine treatment in THP-1 cells, but p38 MAPK inhibitor SB203580 did not. These results suggested that an ERK1/2 pathway plays an important role in the release of IL-8 and TNFα in THP-1 cells treated with terbinafine.
SIGNIFICANCE:The release of inflammatory mediators by terbinafine might be one of the mechanisms underlying immune-mediated liver injury. This in vitro method may be useful to predict adverse inflammatory reactions that lead to drug-induced liver injury.
|MeSH||Antifungal Agents / pharmacology Chemokines / biosynthesis Chemokines / genetics Chemokines / metabolism Cytokines / biosynthesis Cytokines / genetics Cytokines / metabolism Dose-Response Relationship, Drug Extracellular Signal-Regulated MAP Kinases / metabolism Extracellular Signal-Regulated MAP Kinases / physiology* HL-60 Cells Humans Inflammation Mediators / metabolism* Inflammation Mediators / physiology MAP Kinase Signaling System / drug effects* MAP Kinase Signaling System / physiology Monocytes / drug effects* Monocytes / enzymology* Monocytes / metabolism Naphthalenes / pharmacology* Terbinafine|
|WOS Category||MEDICINE, RESEARCH & EXPERIMENTAL PHARMACOLOGY & PHARMACY|
|Human and Animal Cells||THP-1 (RCB1189)|