Role of a histamine 4 receptor as an anti-inflammatory target in carrageenan-induced pleurisy in mice

Immunology. 2014 Jul;142(3):374-83. doi: 10.1111/imm.12257.


The histamine 4 receptor (H4R) is expressed primarily on cells involved in inflammation and immune responses. Despite much research into inflammatory diseases, no drugs with favourable safety profiles are yet available for their treatment. The aim of the present study was to determine the potential anti-inflammatory effect of 4-methylhistamine (4-MeH) or JNJ77777120 (JNJ) and to explore the role of H4R in a mouse model of carrageenan (Cg) -induced pleurisy. A single dose of 4-MeH or JNJ (30 mg/kg) was administered intraperitoneally 1 hr before Cg administration. The results illustrate that both the numbers of CD4(+) , CD25(+) , CD4(+) CD25(+) , GITR(+) , GITR(+) IL-17A(+) -expressing T cells and the levels of T helper type 1 (Th1)/Th17 cytokines were markedly increased in both the Cg-treated and 4-MeH-treated groups, whereas the cytokines produced by Th2 cells were significantly decreased in the same groups. However, JNJ treatment significantly decreased both the number of T-cell subsets and GITR(+) , GITR(+) IL-17A(+) -expressing T cells, and the production of Th1/Th17 cytokines. Further, JNJ up-regulated the expression of the Th2 cytokines. RT-PCR analysis revealed an increased expression of interleukin-1β, tumour necrosis factor-α, monocyte chemoattractant protein-1 and intercellular adhesion molecule-1 in the Cg-treated and 4-MeH-treated groups, which was reduced by treatment with JNJ in lung tissues. Moreover, histological examinations revealed anti-inflammatory effects of JNJ, whereas 4-MeH worsened Cg-induced inflammation. In conclusion, the results of the present work clearly indicate that JNJ possesses important anti-inflammatory properties that are increased in 4-MeH-treated mice, suggesting that H4R are involved in pleurisy and that JNJ has an anti-inflammatory effect in associated disease conditions.

Keywords: 4-methylhistamine dihydrochloride; GITR-expressing cells; JNJ77777120; cytokines; histamine 4 receptor; λ-Carrageenan-induced inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Carrageenan
  • Cytokines / analysis
  • Cytokines / immunology
  • Female
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Indoles / therapeutic use
  • Inflammation / drug therapy
  • Inflammation / immunology
  • Inflammation / metabolism
  • Methylhistamines / chemistry
  • Methylhistamines / pharmacology*
  • Methylhistamines / therapeutic use
  • Mice
  • Mice, Inbred BALB C
  • Molecular Targeted Therapy
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Piperazines / therapeutic use
  • Pleurisy / chemically induced
  • Pleurisy / drug therapy*
  • Pleurisy / immunology
  • Pleurisy / metabolism*
  • Receptors, Histamine / metabolism*
  • Structure-Activity Relationship


  • Anti-Inflammatory Agents, Non-Steroidal
  • Cytokines
  • Indoles
  • Methylhistamines
  • Piperazines
  • Receptors, Histamine
  • 1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine
  • 4-methylhistamine
  • Carrageenan