The histamine H4 receptor (H4R) is a completely novel fourth member of the histamine receptor family. There is a fairly selective expression of H4R on bone marrow and hematopoietic cells known to be involved in inflammatory and immune responses [3]. JNJ-7777120 is an effective and selective non-imidazole histamine H4 receptor antagonist with Ki value of 4.5 nM [4]. JNJ-7777120 has an oral bioavailability of approximately 30% in rats and 100% in dogs, with a half-life of approximately 3 h in both species. In mouse bone marrow-derived mast cells, JNJ-7777120 blocks histamine-induced chemotaxis and calcium influx. Furthermore, it can block the histamine-induced migration of tracheal mast cells from the connective tissue toward the epithelium in mice. In a mouse zymosan-induced peritonitis model which is reported to be mast cell-dependent, JNJ-7777120 significantly blocks neutrophil infiltration suggesting that its effect may be mediated by mast cells[5].
JNJ-7777120 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Atopic dermatitis outer root sheath keratinocytes
10μM
48 hours
Stimulation with histamine or H4R agonist induced proliferation in atopic dermatitis keratinocytes, which was blocked by H4R antagonist JNJ7777120
J Allergy Clin Immunol. 2013 Dec;132(6):1358-67.
H4R-transfected HaCaT keratinocytes
10μM
48 hours
Histamine stimulation induced proliferation in H4R-transfected HaCaT cells, which was blocked by H4R antagonist JNJ7777120
J Allergy Clin Immunol. 2013 Dec;132(6):1358-67.
Human primary neonatal keratinocytes
10μM
48 hours
Stimulation with histamine or H4R agonist 4-MH induced keratinocyte proliferation, which was blocked by H4R-specific antagonist JNJ7777120
J Allergy Clin Immunol. 2013 Dec;132(6):1358-67.
Human retinal endothelial cells (HRECs)
0.1–10 μM
4 hours
To evaluate the effect of JNJ7777120 on angiogenesis, results showed no significant changes in HREC tube formation at concentrations of 0.1 μM, 1 μM, and 10 μM.
Br J Pharmacol. 2014 Aug;171(15):3754-63.
Mouse whole blood
50 μM
4 hours
To evaluate the effect of JNJ-7777120 on LPS-induced TNF production, results showed no inhibition of TNF production by JNJ-7777120 in vitro.
Inflamm Res. 2013 Jun;62(6):599-607.
JNJ-7777120 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6 female mice
Experimental autoimmune encephalomyelitis (EAE) model
Intraperitoneal injection
10 mg/kg
Once daily, starting from day 10 post-immunization until the end of the experiment (up to 28 days)
Evaluate the effect of JNJ7777120 on the clinical course of EAE, showing that JNJ7777120 treatment exacerbated EAE symptoms, increased spinal cord inflammation and demyelination, increased IFN-γ expression, and decreased IL-4 and IL-10 expression
Br J Pharmacol. 2013 Sep;170(1):67-77
BALB/c mice
4T1 TNBC model
Subcutaneous injection
10 mg/kg
Once daily for 15 days
Evaluate the effect of JNJ-7777120 on tumor growth and immune modulation in the 4T1 TNBC model, results showed JNJ-7777120 non-significantly reduced tumor weight and spleen weight, while significantly decreasing the percentage of tumor-infiltrating CD4+ T lymphocytes and Tregs in TDLN
Br J Cancer. 2020 Feb;122(3):348-360.
Mice
Laser-induced choroidal neovascularization (CNV) model
Intravitreous injection
1 μg
Injected immediately after laser injury and again on day 3
To evaluate the effect of JNJ7777120 on CNV volume and pathological vessel leakage, results showed JNJ7777120 significantly reduced laser-induced CNV volume and pathological leakage without causing retinal toxicity.
Br J Pharmacol. 2014 Aug;171(15):3754-63.
BALB/c mice
Carrageenan-induced pleurisy model
Intraperitoneal injection
30 mg/kg
Single dose, lasting 4 hours
To evaluate the anti-inflammatory effects of JNJ-7777120 on carrageenan-induced pleurisy. Results showed that JNJ significantly reduced the number of T-cell subsets, GITR+ and GITR+IL-17A+ cells, and decreased the levels of Th1/Th17 cytokines, while up-regulating the expression of Th2 cytokines.
Immunology. 2014 Jul;142(3):374-83
BALB/c mice
LPS-induced inflammation model
Oral
20 mg/kg
Single dose, LPS administered 30 minutes later
To evaluate the effect of JNJ-7777120 on LPS-induced TNF production, results showed significant inhibition of TNF production by JNJ-7777120.
Inflamm Res. 2013 Jun;62(6):599-607.
BALB/c female mice
OVA-induced sub-chronic airway inflammation model
Oral
5 mg/kg, 20 mg/kg, 50 mg/kg
Once daily, initiated on day 36 through day 58
Therapeutic H4R antagonism inhibited T cell infiltration into 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.
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