Terbinafine stimulates the pro-inflammatory responses in human monocytic THP-1 cells through an ERK signaling pathway.
OBJECTIVE
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.


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.


RESULTS
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.


CONCLUSIONS
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.
Mizuno
Katsuhiko
K
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan.
Fukami
Tatsuki
T
Toyoda
Yasuyuki
Y
Nakajima
Miki
M
Yokoi
Tsuyoshi
T
D000935:Antifungal Agents / Q000494:pharmacology; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism / Q000502:physiology*; D018922:HL-60 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism* / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology*; D000077291:Terbinafine
D000935:Antifungal Agents; D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D009281:Naphthalenes; D048049:Extracellular Signal-Regulated MAP Kinases; D000077291:Terbinafine