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Cytosolic Phospholipase A2 Is Required for Fexofenadine’s Therapeutic Effects against Inflammatory Bowel Disease in Mice

Inflammatory Bowel Disease (IBD) is an autoimmune condition with complicated pathology and diverse clinical signs. TNFα is believed to play a crucial role in the pathogenesis of IBD. We recently identified fexofenadine, a well-known antagonist of histamine H1 receptor, as a novel inhibitor of TNFα s...

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Autores principales: Zhao, Xiangli, Liu, Ronghan, Chen, Yuehong, Hettinghouse, Aubryanna, Liu, Chuanju
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8539349/
https://www.ncbi.nlm.nih.gov/pubmed/34681815
http://dx.doi.org/10.3390/ijms222011155
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author Zhao, Xiangli
Liu, Ronghan
Chen, Yuehong
Hettinghouse, Aubryanna
Liu, Chuanju
author_facet Zhao, Xiangli
Liu, Ronghan
Chen, Yuehong
Hettinghouse, Aubryanna
Liu, Chuanju
author_sort Zhao, Xiangli
collection PubMed
description Inflammatory Bowel Disease (IBD) is an autoimmune condition with complicated pathology and diverse clinical signs. TNFα is believed to play a crucial role in the pathogenesis of IBD. We recently identified fexofenadine, a well-known antagonist of histamine H1 receptor, as a novel inhibitor of TNFα signaling. Additionally, cytosolic phospholipase A2 (cPLA2) was isolated as a binding target of fexofenadine, and fexofenadine-mediated anti-TNF activity relied on cPLA2 in vitro. The objective of this study is to determine whether fexofenadine is therapeutic against chemically-induced murine IBD model and whether cPLA2 and/or histamine H1 receptor is important for fexofenadine’s anti-inflammatory activity in vivo by leveraging various genetically modified mice and chemically induced murine IBD models. Both dextran sulfate sodium- and 2, 4, 6-trinitrobenzene sulfonic acid-induced murine IBD models revealed that orally delivered fexofenadine was therapeutic against IBD, evidenced by mitigated clinical symptoms, decreased secretions of the proinflammatory cytokine IL-6 and IL-1β, lowered intestinal inflammation, and reduced p-p65 and p-IĸBα. Intriguingly, Fexofenadine-mediated protective effects against IBD were lost in cPLA2 deficient mice but not in histamine H1 receptor-deficient mice. Collectively, these findings demonstrate the therapeutic effects of over-the-counter drug Fexofenadine in treating DSS-induced IBD murine and provide first in vivo evidence showing that cPLA2 is required for fexofenadine’s therapeutic effects in murine IBD model and probably other inflammatory and autoimmune diseases as well.
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spelling pubmed-85393492021-10-24 Cytosolic Phospholipase A2 Is Required for Fexofenadine’s Therapeutic Effects against Inflammatory Bowel Disease in Mice Zhao, Xiangli Liu, Ronghan Chen, Yuehong Hettinghouse, Aubryanna Liu, Chuanju Int J Mol Sci Article Inflammatory Bowel Disease (IBD) is an autoimmune condition with complicated pathology and diverse clinical signs. TNFα is believed to play a crucial role in the pathogenesis of IBD. We recently identified fexofenadine, a well-known antagonist of histamine H1 receptor, as a novel inhibitor of TNFα signaling. Additionally, cytosolic phospholipase A2 (cPLA2) was isolated as a binding target of fexofenadine, and fexofenadine-mediated anti-TNF activity relied on cPLA2 in vitro. The objective of this study is to determine whether fexofenadine is therapeutic against chemically-induced murine IBD model and whether cPLA2 and/or histamine H1 receptor is important for fexofenadine’s anti-inflammatory activity in vivo by leveraging various genetically modified mice and chemically induced murine IBD models. Both dextran sulfate sodium- and 2, 4, 6-trinitrobenzene sulfonic acid-induced murine IBD models revealed that orally delivered fexofenadine was therapeutic against IBD, evidenced by mitigated clinical symptoms, decreased secretions of the proinflammatory cytokine IL-6 and IL-1β, lowered intestinal inflammation, and reduced p-p65 and p-IĸBα. Intriguingly, Fexofenadine-mediated protective effects against IBD were lost in cPLA2 deficient mice but not in histamine H1 receptor-deficient mice. Collectively, these findings demonstrate the therapeutic effects of over-the-counter drug Fexofenadine in treating DSS-induced IBD murine and provide first in vivo evidence showing that cPLA2 is required for fexofenadine’s therapeutic effects in murine IBD model and probably other inflammatory and autoimmune diseases as well. MDPI 2021-10-15 /pmc/articles/PMC8539349/ /pubmed/34681815 http://dx.doi.org/10.3390/ijms222011155 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zhao, Xiangli
Liu, Ronghan
Chen, Yuehong
Hettinghouse, Aubryanna
Liu, Chuanju
Cytosolic Phospholipase A2 Is Required for Fexofenadine’s Therapeutic Effects against Inflammatory Bowel Disease in Mice
title Cytosolic Phospholipase A2 Is Required for Fexofenadine’s Therapeutic Effects against Inflammatory Bowel Disease in Mice
title_full Cytosolic Phospholipase A2 Is Required for Fexofenadine’s Therapeutic Effects against Inflammatory Bowel Disease in Mice
title_fullStr Cytosolic Phospholipase A2 Is Required for Fexofenadine’s Therapeutic Effects against Inflammatory Bowel Disease in Mice
title_full_unstemmed Cytosolic Phospholipase A2 Is Required for Fexofenadine’s Therapeutic Effects against Inflammatory Bowel Disease in Mice
title_short Cytosolic Phospholipase A2 Is Required for Fexofenadine’s Therapeutic Effects against Inflammatory Bowel Disease in Mice
title_sort cytosolic phospholipase a2 is required for fexofenadine’s therapeutic effects against inflammatory bowel disease in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8539349/
https://www.ncbi.nlm.nih.gov/pubmed/34681815
http://dx.doi.org/10.3390/ijms222011155
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