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

• Published in: Immunobiology (1979) 2015-07, Vol.220 (7), p.889-898
• Main Authors: Ahmad, Sheikh Fayaz, Ansari, Mushtaq Ahmad, Zoheir, Khairy M.A, Bakheet, Saleh A, Korashy, Hesham M, Nadeem, Ahmed, Ashour, Abdelkader E, Attia, Sabry M
• Format: Article
• Language: English
• Subjects: 4-Methylhistamine dihydrochloride; Advanced Basic Science; Allergy and Immunology; Animals; Anti-Inflammatory Agents - pharmacology; Enzyme Activation; Female; Gene Expression Regulation; Histamine 4 receptor; Histamine Agonists - pharmacology; Histamine Antagonists - pharmacology; I-kappa B Proteins - blood; Indoles - pharmacology; Inflamed rat knee; Inflammation - diagnosis; Inflammation - immunology; Inflammation - pathology; Interleukin-1beta - genetics; JAK-STAT signaling pathway; Janus Kinase 1 - genetics; Janus Kinase 1 - metabolism; JNJ77777120; Knee Joint - immunology; Knee Joint - pathology; Lipopolysaccharide; Lipopolysaccharides; Methylhistamines - pharmacology; NF-kappa B - blood; NF-kappa B - genetics; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha; Piperazines - pharmacology; Rats; Rats, Wistar; Receptors, G-Protein-Coupled - genetics; Receptors, Histamine - genetics; Receptors, Histamine H4; RNA, Messenger - biosynthesis; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Tumor necrosis factor-alpha; Tumor Necrosis Factor-alpha - blood; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0171-2985; 1878-3279
• DOI: 10.1016/j.imbio.2015.01.008

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 18 h before a single dose of 4-MeH or JNJ (30 mg/kg) was administered intraperitoneally (i.p.), both followed by intra-articular (i.a.) injection of LPS 2 h 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.