Itraconazole inhibits TNF-α-induced CXCL10 expression in oral fibroblasts.
OBJECTIVE
Itraconazole (ICZ) has a broad spectrum of antifungal activity including a wide range of Candida spp. TNF-α, an inflammatory cytokine associated with Th1-mediated oral inflammatory disease, enhances inflammatory mediators, such as CXCR3-agonistic chemokines including CXCL10. We examined the anti-inflammatory potential of ICZ against TNF-α-induced chemokines in oral fibroblasts.


METHODS
We investigated the effects of ICZ on mRNA expressions of various TNF-α-induced chemokines in immortalized oral keratinocytes (RT7) and oral fibroblasts (GT1) using quantitative PCR analysis. Subsequently, the effects of ICZ and fluconazole (FLZ) on TNF-α-induced CXCL10 proteins in GT1 and primary fibroblasts were examined using enzyme-linked immunosorbent assays (ELISA). The effect of ICZ on signal transduction protein phosphorylation involved in CXCL10 production from TNF-α-stimulated GT1 was examined by western blotting.


RESULTS
ICZ inhibited TNF-α-induced CXCL10 mRNA in GT1, but not RT7. Although ICZ did not affect TNF-α-induced IL-8 mRNA, the mRNAs of TNF-α-induced CXCR3-agonistic chemokines such as CXCL9 and CXCL11 were inhibited by ICZ in GT1. TNF-α-induced CXCL10 protein production in GT1 and primary fibroblasts was inhibited by ICZ, but not FLZ. Finally, ICZ inhibited TNF-α-induced phosphorylation of c-JUN, which is related to CXCL10 production by TNF-α-stimulated GT1.


CONCLUSIONS
ICZ may be useful as therapy for Th1-mediated oral inflammatory disease.
Department of Oral and Maxillofacial Surgery, Division of Cervico-Gnathostmatology, Programs for Applied Biomedicine, Graduate School of Biomedical Sciences, Hiroshima University, Minami-Ku, Hiroshima, Japan.
K
K
Ohta
Y
Y
Ishida
A
A
Fukui
H
H
Nishi
T
T
Naruse
M
M
Takechi
N
N
Kamata
D000935:Antifungal Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D054357:Chemokine CXCL10 / Q000096:biosynthesis*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D015725:Fluconazole / Q000494:pharmacology; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology*; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009055:Mouth / Q000166:cytology*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000935:Antifungal Agents; D054357:Chemokine CXCL10; D014409:Tumor Necrosis Factor-alpha; D017964:Itraconazole; D015725:Fluconazole
CXCL10; TNF-α; itraconazole; oral fibroblasts