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.

• Main Authors: Ahmad, Sheikh Fayaz, Ahmad Ansari, Mushtaq, Zoheir, Khairy M.A., A.Bakheet, Saleh, M.Korashy, Hesham, Nadeem, Ahmed, Ashour, Abdelkader Elbadawy Abbas, Attia, Sabry M.
• Format: Article
• Language: English; English
• Published: Elsevier 2015
• Subjects: RM300 Drugs and their action
• Online Access: http://irep.iium.edu.my/66890/1/Regulation%20of%20TNF-%CE%B1%20and%20NF-%CE%BAB%20activation%20through%20the%20JAK%20STAT%20signaling%20pathway%20downstream%20of%20histamine%204%20receptor%20in%20a%20rat%20model%20of%20LPS-induced%20joint%20inflammation..pdf; http://irep.iium.edu.my/66890/7/66890_Scopus.pdf; http://irep.iium.edu.my/66890/; https://www.journals.elsevier.com/immunobiology/

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.