Monoamine Oxidase-B Inhibitor Reduction in Pro-Inflammatory Cytokines Mediated by Inhibition of cAMP-PKA/EPAC Signaling

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...

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Autores principales:	Edward E. Putnins, Verena Goebeler, Mahyar Ostadkarampour
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	monoamine oxidases monoamine oxidase inhibitors lipopolysaccharide inflammation cytokines cAMP Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/a3437439d7814df39575ec0c56ff20e9
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spelling	oai:doaj.org-article:a3437439d7814df39575ec0c56ff20e92021-11-17T06:27:25ZMonoamine Oxidase-B Inhibitor Reduction in Pro-Inflammatory Cytokines Mediated by Inhibition of cAMP-PKA/EPAC Signaling1663-981210.3389/fphar.2021.741460https://doaj.org/article/a3437439d7814df39575ec0c56ff20e92021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.741460/fullhttps://doaj.org/toc/1663-9812Mucosal 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.Edward E. PutninsVerena GoebelerMahyar OstadkarampourFrontiers Media S.A.articlemonoamine oxidasesmonoamine oxidase inhibitorslipopolysaccharideinflammationcytokinescAMPTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	monoamine oxidases monoamine oxidase inhibitors lipopolysaccharide inflammation cytokines cAMP Therapeutics. Pharmacology RM1-950
spellingShingle	monoamine oxidases monoamine oxidase inhibitors lipopolysaccharide inflammation cytokines cAMP Therapeutics. Pharmacology RM1-950 Edward E. Putnins Verena Goebeler Mahyar Ostadkarampour Monoamine Oxidase-B Inhibitor Reduction in Pro-Inflammatory Cytokines Mediated by Inhibition of cAMP-PKA/EPAC Signaling
description	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.
format	article
author	Edward E. Putnins Verena Goebeler Mahyar Ostadkarampour
author_facet	Edward E. Putnins Verena Goebeler Mahyar Ostadkarampour
author_sort	Edward E. Putnins
title	Monoamine Oxidase-B Inhibitor Reduction in Pro-Inflammatory Cytokines Mediated by Inhibition of cAMP-PKA/EPAC Signaling
title_short	Monoamine Oxidase-B Inhibitor Reduction in Pro-Inflammatory Cytokines Mediated by Inhibition of cAMP-PKA/EPAC Signaling
title_full	Monoamine Oxidase-B Inhibitor Reduction in Pro-Inflammatory Cytokines Mediated by Inhibition of cAMP-PKA/EPAC Signaling
title_fullStr	Monoamine Oxidase-B Inhibitor Reduction in Pro-Inflammatory Cytokines Mediated by Inhibition of cAMP-PKA/EPAC Signaling
title_full_unstemmed	Monoamine Oxidase-B Inhibitor Reduction in Pro-Inflammatory Cytokines Mediated by Inhibition of cAMP-PKA/EPAC Signaling
title_sort	monoamine oxidase-b inhibitor reduction in pro-inflammatory cytokines mediated by inhibition of camp-pka/epac signaling
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/a3437439d7814df39575ec0c56ff20e9
work_keys_str_mv	AT edwardeputnins monoamineoxidasebinhibitorreductioninproinflammatorycytokinesmediatedbyinhibitionofcamppkaepacsignaling AT verenagoebeler monoamineoxidasebinhibitorreductioninproinflammatorycytokinesmediatedbyinhibitionofcamppkaepacsignaling AT mahyarostadkarampour monoamineoxidasebinhibitorreductioninproinflammatorycytokinesmediatedbyinhibitionofcamppkaepacsignaling
_version_	1718425879137222656

Monoamine Oxidase-B Inhibitor Reduction in Pro-Inflammatory Cytokines Mediated by Inhibition of cAMP-PKA/EPAC Signaling

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