Journal
IMMUNOBIOLOGY
Volume 220, Issue 7, Pages 889-898Publisher
ELSEVIER GMBH
DOI: 10.1016/j.imbio.2015.01.008
Keywords
Histamine 4 receptor; JNJ77777120; 4-Methylhistamine dihydrochloride; Tumor necrosis factor-alpha; Inflamed rat knee; Lipopolysaccharide; JAK-STAT signaling pathway
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Funding
- Deanship of Scientific Research at King Saud University [RGP-VPP-120]
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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-alpha, NF-kappa B, and IkB-alpha levels were measured via flow cytometry. Additionally, we assessed the effects of H4R engagement on the expression of IL-1 beta, TNF-alpha, and NF-kappa B mRNAs and the protein levels of TNF-alpha, NF-kappa B, JAK-1, and STAT-3 in the inflamed knee tissue. These results revealed increased TNF-alpha and NF-kappa B expression and decreased IkB-alpha levels in both the LPS alone and 4-MeH treated groups in whole blood and synovial fluid. Further, IL-1 beta, TNF-alpha, and NF-kappa B mRNA levels were significantly increased and western blot analysis confirmed increased expression of TNF-alpha, NF-kappa B, 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. (C) 2015 Elsevier GmbH. All rights reserved.
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