title: Involvement of histamine 4 receptor in the pathogenesis and progression of rheumatoid arthritis.
abstract: Rheumatoid arthritis (RA) is one of the major autoimmune diseases with a global prevalence. Despite significant research into this disease, no drugs with acceptable safety profiles are yet available for its treatment. We investigated the possible anti-arthritic effects of the 4-methylhistamine (4-MeH) histamine 4 receptor (H4R) agonist and the JNJ77777120 (JNJ) H4R antagonist to explore the role of H4R in a mouse model of collagen antibody-induced arthritis (CAIA). Arthritis was induced via intravenous (tail vein) injection of Balb/c mice with a 5-clone cocktail of mAbs against collagen type II, followed by LPS, and the effects of treatment with 4-MeH or JNJ (30 mg kg(-1), i.p, twice daily) for 7 days (prophylactic or therapeutic regimens) were assessed. The results revealed increased paw edema, arthritic scores, joint histological inflammatory damage and matrix metalloproteinase-3 levels and high levels of Th1 pro-inflammatory cytokine mRNA and serum proteins in CAIA mice or following H4R activation via 4-MeH. Additionally, 4-MeH efficiently increased expression levels of NF-κB p65. JNJ-treated mice showed a substantial reduction in all the previously mentioned effects, with a similar trend being observed under prophylactic and therapeutic treatment regimens. The results of the present work indicate that JNJ exhibits significant anti-inflammatory and anti-arthritic activities, demonstrating the clear involvement of H4R antagonism in the pathogenesis and progression of RA.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, PO Box 11451, Riyadh, Saudi Arabia Department of Pharmacology and Toxicology, College of Pharmacy, Al-Azhar University, Cairo 11751, Egypt.
authors.forename: Adel R A
authors.initials: AR
authors.lastname: Abd-Allah
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, PO Box 11451, Riyadh, Saudi Arabia.
authors.forename: Sheikh Fayaz
authors.initials: SF
authors.lastname: Ahmad
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, PO Box 11451, Riyadh, Saudi Arabia.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Alrashidi
authors.affiliation: Department of Pathology, Faculty of Medicine (Girls), Al-Azhar University, Cairo 11751, Egypt.
authors.forename: Hala E
authors.initials: HE
authors.lastname: Abdel-Hamied
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, PO Box 11451, Riyadh, Saudi Arabia Department of Cell Biology, National Research Centre, Cairo 12622, Egypt.
authors.forename: Khairy M A
authors.initials: KM
authors.lastname: Zoheir
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, PO Box 11451, Riyadh, Saudi Arabia.
authors.forename: Abdelkader E
authors.initials: AE
authors.lastname: Ashour
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, PO Box 11451, Riyadh, Saudi Arabia.
authors.forename: Saleh A
authors.initials: SA
authors.lastname: Bakheet
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, PO Box 11451, Riyadh, Saudi Arabia Department of Pharmacology and Toxicology, College of Pharmacy, Al-Azhar University, Cairo 11751, Egypt.
authors.forename: Sabry M
authors.initials: SM
authors.lastname: Attia
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016130:Immunophenotyping; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects; D007274:Injections, Intraperitoneal; D008213:Lymphocyte Activation / Q000187:drug effects; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D008761:Methylhistamines / Q000008:administration & dosage* / Q000009:adverse effects; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D018417:Th1 Cells / Q000276:immunology*
chemical_list: D016207:Cytokines; C418607:HRH4 protein, human; D007211:Indoles; D008761:Methylhistamines; D016328:NF-kappa B; D010879:Piperazines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; C484309:1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine; C025566:4-methylhistamine; D019278:Matrix Metalloproteinase 3
keywords: 4-methylhistamine dihydrochloride; JNJ77777120; NF-κB p65; T-cell subsets; chemokines; collagen antibody-induced arthritis; cytokines; histamine 4 receptor; interleukin; mRNA expression; regulatory T cells