title: Regulation of TNF-α and NF-κB activation through the JAK/STAT signaling pathway downstream of histamine 4 receptor in a rat model of LPS-induced joint inflammation.
abstract: Histamine 4 receptor (H4R) is a novel target for the pharmacological modulation of histamine-mediated immune signals during inflammatory diseases. The purpose of this study was to assess the effects of the H4R agonist 4-methylhistamine dihydrochloride (4-MeH) and antagonist JNJ7777120 (JNJ) in the inflamed rat knee. Animals were fasted for 18h before a single dose of 4-MeH or JNJ (30mg/kg) was administered intraperitoneally (i.p.), both followed by intra-articular (i.a.) injection of LPS 2h later. Blood and synovial fluid were collected after a short incubation period and TNF-α, NF-κB, and IkB-α levels were measured via flow cytometry. Additionally, we assessed the effects of H4R engagement on the expression of IL-1β, TNF-α, and NF-κB mRNAs and the protein levels of TNF-α, NF-κB, JAK-1, and STAT-3 in the inflamed knee tissue. These results revealed increased TNF-α and NF-κB expression and decreased IkB-α levels in both the LPS alone and 4-MeH treated groups in whole blood and synovial fluid. Further, IL-1β, TNF-α, and NF-κB mRNA levels were significantly increased and western blot analysis confirmed increased expression of TNF-α, NF-κB, JAK-1, and STAT-3 in both LPS and 4-MeH treatment groups. Furthermore, these increases were completely inhibited in the inflamed knee tissue of the JNJ-treated group. Thus, the inhibition of inflammatory mediators and signaling pathways by the H4R antagonist JNJ suggests the anti-arthritic importance of this molecule.
authors: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Electronic address: s_fayazahmad@yahoo.com.
authors: Sheikh Fayaz
authors: SF
authors: Ahmad
authors: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors: Mushtaq Ahmad
authors: MA
authors: Ansari
authors: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; Department of Cell Biology, National Research Centre, Cairo, Egypt.
authors: Khairy M A
authors: KM
authors: Zoheir
authors: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors: Saleh A
authors: SA
authors: Bakheet
authors: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors: Hesham M
authors: HM
authors: Korashy
authors: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors: Ahmed
authors: A
authors: Nadeem
authors: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors: Abdelkader E
authors: AE
authors: Ashour
authors: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; Department of Pharmacology and Toxicology, College of Pharmacy, Al-Azhar University, Cairo, Egypt.
authors: Sabry M
authors: SM
authors: Attia
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D004789:Enzyme Activation; D005260:Female; D005786:Gene Expression Regulation; D017442:Histamine Agonists / Q000494:pharmacology; D006633:Histamine Antagonists / Q000494:pharmacology; D020672:I-kappa B Proteins / Q000097:blood; D007211:Indoles / Q000494:pharmacology; D007249:Inflammation / Q000175:diagnosis / Q000276:immunology / Q000473:pathology*; D053583:Interleukin-1beta / Q000235:genetics; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism; D007719:Knee Joint / Q000276:immunology / Q000473:pathology*; D008070:Lipopolysaccharides; D008761:Methylhistamines / Q000494:pharmacology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D011968:Receptors, Histamine / Q000235:genetics*; D000074040:Receptors, Histamine H4; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D017442:Histamine Agonists; D006633:Histamine Antagonists; C498828:Hrh4 protein, rat; D020672:I-kappa B Proteins; C000594089:IL1B protein, rat; D007211:Indoles; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D008761:Methylhistamines; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D010879:Piperazines; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; C484309:1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine; C025566:4-methylhistamine; C507906:Jak1 protein, rat; D053613:Janus Kinase 1
keywords: 4-Methylhistamine dihydrochloride; Histamine 4 receptor; Inflamed rat knee; JAK-STAT signaling pathway; JNJ77777120; Lipopolysaccharide; Tumor necrosis factor-alpha