Abstract
Miconazole is effective in treating inflammatory skin conditions and has well-established antifungal effects. To elucidate the underlying mechanisms mediating its additional beneficial effects, we assessed whether miconazole influences the inflammation induced by 27-hydroxycholesterol (27OHChol), an oxygenated cholesterol derivative with high proinflammatory activity, using THP-1 monocytic cells. Miconazole dose-dependently inhibited the expression of proinflammatory markers, including CCL2 and CCR5 ligands such as CCL3 and CCL4, and impaired the migration of monocytic cells and CCR5-positive T cells. In the presence of 27OHChol, miconazole decreased CD14 surface levels and considerably weakened the lipopolysaccharide response. Furthermore, miconazole blocked the release of soluble CD14 and impaired the transcription of the matrix metalloproteinase-9 gene and secretion of its active gene product. Additionally, it downregulated the expression of ORP3 and restored the endocytic function of THP-1 cells. Collectively, these findings indicate that miconazole regulates the 27OHChol-induced expression of proinflammatory molecules in monocytic cells, thereby suppressing inflammation in an oxysterol-rich milieu.
Highlights
Miconazole, an imidazole antifungal agent, is topically applied to the skin or mucous membranes for treating fungal infections (Barasch and Griffin, 2008; Zhang et al, 2016)
To determine whether miconazole affects inflammatory responses, we examined its effects on 27OHChol-induced chemokine expression
27OHChol-induced stimulation of THP-1 cells upregulated the expression of CCL2, CCL3, and CCL4 chemokines at both mRNA and protein levels; this increase was suppressed by miconazole, as determined with Quantitative Reverse Transcription–Polymerase Chain Reaction (qRT-PCR) and Enzyme-Linked Immunosorbent Assay (ELISA) (Figure 1A,B)
Summary
Miconazole, an imidazole antifungal agent, is topically applied to the skin or mucous membranes for treating fungal infections (Barasch and Griffin, 2008; Zhang et al, 2016). The imidazole antifungal agents inhibit the synthesis of ergosterol, the most abundant sterol in the fungal cell membrane, regulate permeability and fluidity, and induce the accumulation of reactive oxygen species within the fungal organism, thereby exerting fungistatic or fungicidal effects (Barasch and Griffin, 2008). Previous studies have revealed the anti-inflammatory activity of miconazole at therapeutic equivalent doses by employing cell and animal models (Zhang et al, 2019; Yeo et al, 2020). Underlying mechanisms mediating these anti-inflammatory effects of miconazole remain elusive
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