Abstract
Mucosal epithelial cell integrity is an important component of innate immunity and it protects the host from an environment rich in microorganisms. Virulence factors from Gram-negative bacteria [e.g. lipopolysaccharide (LPS)] induce significant pro-inflammatory cytokine expression. Monoamine oxidase (MAO) inhibitors reduce cytokine expression in a variety of inflammatory models and may therefore have therapeutic potential for a number of inflammatory diseases. We tested the anti-inflammatory therapeutic potential of a recently developed reversible MAO-B inhibitor (RG0216) with reduced transport across the blood–brain barrier. In an epithelial cell culture model, RG0216 significantly decreased LPS-induced interleukin (IL)-6 and IL-1β gene and protein expression and was as effective as equimolar concentrations of deprenyl (an existing irreversible MAO-B inhibitor). Hydrogen peroxide and modulating dopamine receptor signaling had no effect on cytokine expression. We showed that LPS-induced expression of IL-6 and IL-1β was cAMP dependent, that IL-6 and IL-1β expression were induced by direct cAMP activation (forskolin) and that RG0216 and deprenyl effectively reduced cAMP-mediated cytokine expression. Targeted protein kinase A (PKA) and Exchange Protein Activated by cAMP (EPAC) activation regulated IL-6 and IL-1β expression, albeit in different ways, but both cytokines were effectively decreased with RG0216. RG0216 reduction of LPS-induced cytokine expression occurred by acting downstream of the cAMP-PKA/EPAC signaling cascade. This represents a novel mechanism by which MAO-B selective inhibitors regulate LPS-induced IL-6 and IL-1β expression.
Highlights
The mucosal epithelium provides a functional barrier in areas such as the oral cavity, gastrointestinal track, lungs and reproductive tracts
We examined the in vitro anti-inflammatory potential of RG0216 using a cervical epithelial cell line (SiHa) that only expresses Monoamine oxidase (MAO)-B, and LPS was used as the innate immune driver of inflammation
MAO-B protein was expressed in SiHa cell lysates (Figure 1A)
Summary
The mucosal epithelium provides a functional barrier in areas such as the oral cavity, gastrointestinal track, lungs and reproductive tracts. Induction of P/DAMP signaling drives epithelial cells to express pro-inflammatory cytokines and MAO-B Inhibitor Regulation of Cytokines chemokines such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8) (Borish and Steinke, 2003; Kugelberg, 2014; Groeger and Meyle, 2019; Plemmenos et al, 2021). Significant evidence supports that reduction of monoamine oxidase enzyme function by MAO inhibitors decreases innate immune-based cytokine signaling and positively improves disease progression (Ostadkarampour and Putnins, 2021). Monoamine oxidases are mammalian flavoenzymes that are associated with the mitochondrial membrane and catalyze deamination of biogenic and dietary amines, monoamine hormones, neurotransmitters such as serotonin, dopamine, (nor)epinephrine and trace amines such as tyramine, tryptamine and 2-phenylethylamine (Youdim et al, 2006; Bortolato et al, 2008; Edmondson and Binda, 2018; Tipton, 2018). Dopamine, (nor)epinephrine, tryptamine and tyramine are oxidized by both (Youdim et al, 2006)
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