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

Xiangli Zhao,Yuehong Chen,Ronghan Liu,Chuanju Liu,Aubryanna Hettinghouse

doi:10.3390/ijms222011155

Abstract

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.

Highlights

Autoimmune diseases include a wide range of conditions characterized by loss of immune self-tolerance and target organ attack [1]
Implementation of our Inflammatory Bowel Disease (IBD) models in histamine H1-receptor (H1R) knockout (KO) and cytosolic phospholipase A2 (cPLA2) KO mice, we clearly demonstrated that the therapeutic effect of FFD on IBD was predominately dependent on cPLA2, but not on its well-known target H1R
Since we found the secretion level of IL-6 and IL-1β were dramatically decreased after FFD or TFD treatment in our IBD mice models, we assessed the level of phospho-p65 and phospho-IκBα via immunohistochemistry staining of FFD- or TFD-treated IBD model mice

Summary

Introduction

Autoimmune diseases include a wide range of conditions characterized by loss of immune self-tolerance and target organ attack [1]. Inflammatory Bowel Disease (IBD), including ulcerative colitis and Crohn’s disease, is one of the most common autoimmune diseases [2]. TNFα is involved in the onset and progression of many inflammatory diseases, and elevated expression of TNFα is believed to play an important role in the pathogenesis of IBD [5]. Anti-TNFα therapy has been approved to use in Crohn’s disease since 1998, including monoclonal antibodies or fragments thereof directed against TNF molecules, such as Infliximab (IFX), Adalimumab (ADA), Certolizumab pegol (Cimzia) [9,10]. Anti-TNFα agents have proven efficacious treatments in immune-mediated inflammatory conditions, not all patients respond to treatment [7,11]. Our screens led to the identification of Terfenadine (TFD) and its active metabolite Fexofenadine (FFD) as novel inhibitors of TNFα signaling [15]

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