Histamine mediates its physiological function through binding to four known histamine receptors. Here, we describe the first selective antagonist of the histamine H 4 receptor, the newest member of the histamine receptor family, and provide evidence that such antagonists have anti-inflammatory activity in vivo.
Histamine is an important inflammatory mediator that is released in airways during an asthmatic response. However, current antihistamine drugs are not effective in controlling the disease. The discovery of the histamine H4 receptor (H4R) prompted us to reinvestigate the role of histamine in pulmonary allergic responses. H4R-deficient mice and mice treated with H4R antagonists exhibited decreased allergic lung inflammation, with decreases in infiltrating lung eosinophils and lymphocytes and decreases in Th2 responses. Ex vivo restimulation of T cells showed decreases in IL-4, IL-5, IL-13, IL-6, and IL-17 levels, suggesting that T cell functions were disrupted. In vitro studies indicated that blockade of the H4R on dendritic cells leads to decreases in cytokine and chemokine production and limits their ability to induce Th2 responses in T cells. This work suggests that the H4R can modulate allergic responses via its influence on T cell activation. The study expands the known influences of histamine on the immune system and highlights the therapeutic potential of H4R antagonists in allergic conditions.
Leukotriene A 4 hydrolase (LTA 4 H) catalyzes production of the proinflammatory lipid mediator, leukotriene (LT) B 4 , which is implicated in a number of inflammatory diseases. We have identified a potent and selective inhibitor of both the epoxide hydrolase and aminopeptidase activities of recombinant human LTA 4 H (IC 50 , approximately 10 nM). In a murine model of arachidonic acid-induced ear inflammation, the LTA 4 H inhibitor, JNJ-26993135 (1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidine-4-carboxylic acid), dose-dependently inhibited ex vivo LTB 4 production in blood, in parallel with dose-dependent inhibition of neutrophil influx (ED 50 , 1-3 mg/kg) and ear edema. In murine whole blood and in zymosan-induced peritonitis, JNJ-26993135 selectively inhibited LTB 4 production, without affecting cysteinyl leukotriene production, while maintaining or increasing production of the anti-inflammatory mediator, lipoxin (LX) A 4 . The 5-lipoxygenase (5-LO) inhibitor zileuton showed inhibition of LTB 4 , LTC 4 , and LXA 4 production. Although zileuton inhibited LTB 4 production in the peritonitis model more effectively than the LTA 4 H inhibitor, the influx of neutrophils into the peritoneum after 1 and 2 h was significantly higher in zileuton-versus JNJ-26993135-treated animals. This difference may have been mediated by the increased LXA 4 levels in the presence of the LTA 4 H inhibitor. The selective inhibition of LTB 4 production by JNJ-26993135, while increasing levels of the anti-inflammatory mediator, LXA 4 , may translate to superior therapeutic efficacy versus 5-LO or 5-LO-activating protein inhibitors in LTB 4 -mediated inflammatory diseases.
BackgroundAirway remodeling and dysfunction are characteristic features of asthma thought to be caused by aberrant production of Th2 cytokines. Histamine H4 receptor (H4R) perturbation has previously been shown to modify acute inflammation and Th2 cytokine production in a murine model of asthma. We examined the ability of H4R antagonists to therapeutically modify the effects of Th2 cytokine production such as goblet cell hyperplasia (GCH), and collagen deposition in a sub-chronic model of asthma. In addition, effects on Th2 mediated lung dysfunction were also determined.MethodsMice were sensitized to ovalbumin (OVA) followed by repeated airway challenge with OVA. After inflammation was established mice were dosed with the H4R antagonist, JNJ 7777120, or anti-IL-13 antibody for comparison. Airway hyperreactivity (AHR) was measured, lungs lavaged and tissues collected for analysis.ResultsTherapeutic H4R antagonism inhibited T cell infiltration in to the lung and decreased Th2 cytokines IL-13 and IL-5. IL-13 dependent remodeling parameters such as GCH and lung collagen were reduced. Intervention with H4R antagonist also improved measures of central and peripheral airway dysfunction.ConclusionsThese data demonstrate that therapeutic H4R antagonism can significantly ameliorate allergen induced, Th2 cytokine driven pathologies such as lung remodeling and airway dysfunction. The ability of H4R antagonists to affect these key manifestations of asthma suggests their potential as novel human therapeutics.
ObjectiveThe histamine H4 receptor (H4R) has been shown to drive inflammatory responses in models of asthma, colitis and dermatitis, and in these models it appears to affect both innate and adaptive immune responses. In this study, we used both H4R-deficient mice and a specific H4R antagonist, JNJ 28307474, to investigate the involvement of the H4R in mouse arthritis models.MethodsH4R-deficient mice and wild-type mice administered the H4R antagonist were studied in models of collagen antibody-induced arthritis (CAIA) and collagen-induced arthritis (CIA). The impact on Th17 cells was assessed by restimulation of inguinal lymphocytes in the disease or immunisation models and with in vitro stimulation of whole blood.ResultsBoth H4R-deficient mice and mice treated with the H4R antagonist exhibited reduced arthritis disease severity in both CAIA and CIA models. This was evident from the reduction in disease score and in joint histology. In the CIA model, treatment with the H4R antagonist reduced the number of interleukin (IL)-17 positive cells in the lymph node and the total production of IL-17. Th17 cell development in vivo was reduced in H4R-deficient mice or in mice treated with an H4R antagonist. Finally, treatment of both mouse and human blood with an H4R antagonist reduced the production of IL-17 when cells were stimulated in vitro.ConclusionsThese results implicate the H4R in disease progression in arthritis and in the production of IL-17 from Th17 cells. This work supports future clinical exploration of H4R antagonists for the treatment of rheumatoid arthritis.
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