title: Roxatidine attenuates mast cell-mediated allergic inflammation via inhibition of NF-κB and p38 MAPK activation.
abstract: Roxatidine is an active metabolite of roxatidine acetate hydrochloride which is a histamine H2-receptor antagonist that is used to treat gastric and duodenal ulcers. In this study, we investigated the anti-allergic inflammatory effects and the underlying molecular mechanism of roxatidine in phorbol 12-myristate 13-acetate and calcium ionophore (PMACI)-stimulated human mast cells-1 (HMC-1), compound 48/80-induced anaphylactic animal model and chemical allergen-induced contact hypersensitivity (CHS) models. Roxatidine suppressed the mRNA and protein expression of inflammatory cytokines such as TNF-α, IL-6, and IL-1β in PMACI-stimulated HMC-1 and compound 48/80-induced anaphylactic mice. In addition, roxatidine attenuated PMACI-induced nuclear translocation of NF-κB and the phosphorylation of MKK3/6 and MK2, which are both involved in the p38 MAPK pathway. Furthermore, we observed that roxatidine suppressed the activation of caspase-1, an IL-1β converting enzyme, in PMACI-stimulated HMC-1 and compound 48/80-induced anaphylactic mice. In CHS model, roxatidine significantly reduced ear swelling, increased number of mast cells, production levels of cytokines and migration of dendritic cells. Our findings provide evidence that the anti-allergic inflammatory properties of roxatidine are mediated by the inhibition of NF-κB and caspase-1 activation, p38 MAPK pathway and mast cell-derived cytokine production. Taken together, the in vitro and in vivo anti-allergic inflammatory effects suggest a possible therapeutic application of roxatidine in allergic inflammatory diseases.
authors.affiliation: Catholic Precision Medicine Research Center, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.
authors.forename: Minho
authors.initials: M
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, College of Korean Medicine, Sangji University, Gangwon-do 220-702, Republic of Korea.
authors.forename: Na Young
authors.initials: NY
authors.lastname: Lee
authors.affiliation: Catholic Precision Medicine Research Center, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.
authors.forename: Kyung-Sook
authors.initials: KS
authors.lastname: Chung
authors.affiliation: Department of Pharmacology, College of Korean Medicine, Sangji University, Gangwon-do 220-702, Republic of Korea.
authors.forename: Se-Yun
authors.initials: SY
authors.lastname: Cheon
authors.affiliation: Department of Pharmaceutical Biochemistry, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, College of Korean Medicine, Sangji University, Gangwon-do 220-702, Republic of Korea.
authors.forename: Hyo-Jin
authors.initials: HJ
authors.lastname: An
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D015252:Deoxyribonucleases, Type II Site-Specific / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006635:Histamine H2 Antagonists / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology* / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000502:physiology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D016207:Cytokines; D006635:Histamine H2 Antagonists; D018836:Inflammation Mediators; D016328:NF-kappa B; D010880:Piperidines; D048051:p38 Mitogen-Activated Protein Kinases; C048066:endodeoxyribonuclease PmaCI; D015252:Deoxyribonucleases, Type II Site-Specific; D020170:Caspase 1; C053742:roxatidine acetate