Antagonism of the histamine H4 receptor reduces LPS-induced TNF production in vivo
Open Access
- 27 March 2013
- journal article
- research article
- Published by Springer Science and Business Media LLC in Inflammation Research
- Vol. 62 (6), 599-607
- https://doi.org/10.1007/s00011-013-0612-5
Abstract
Antagonism of the histamine H4 receptor (H4R) has been shown to be anti-inflammatory in a number of preclinical disease models, however the exact mechanisms behind this are still being uncovered. In vitro, the receptor interacts with TLR and impacts inflammatory mediator production from a number of different cell types. Here it is shown that this interaction also occurs in vivo. Wild-type and H4R deficient BALB/c mice received an i.p. injection of LPS in PBS in conjunction with p.o. JNJ 7777120 or JNJ 28307474 (H4R antagonists). Two hours later blood was collected and TNF was measured. Two different H4R antagonists inhibited LPS-induced TNF production in mice and this production was also reduced in H4R-deficient mice. The TNF mRNA analysis showed that the major source of the cytokine was the liver and not blood, and that the H4R antagonist only reduced the expression levels in the liver. Depletion or inactivation of macrophages reduced the TNF levels and eliminated the H4R sensitivity. Treatment with an H4R antagonist also reduced LPS-induced liver injury and blocked LPS-enhanced lung inflammation in mice. The data support an interaction between H4R and TLR activation in vivo that can drive inflammatory responses.Keywords
This publication has 25 references indexed in Scilit:
- The Histamine H4 Receptor Is Highly Expressed on Plasmacytoid Dendritic Cells in Psoriasis and Histamine Regulates Their Cytokine Production and MigrationJournal of Investigative Dermatology, 2011
- Histamine H4 receptor activation enhances LPS-induced IL-6 production in mast cells via ERK and PI3K activationEuropean Journal of Immunology, 2011
- Histamine H4 receptor activation on human slan-dendritic cells down-regulates their pro-inflammatory capacityImmunology, 2010
- Histamine H4 receptor antagonism diminishes existing airway inflammation and dysfunction via modulation of Th2 cytokinesRespiratory Research, 2010
- The Histamine H4 Receptor Mediates Inflammation and Pruritus in Th2-Dependent Dermal InflammationJournal of Investigative Dermatology, 2010
- Immunomodulating effects of endotoxin in mouse models of allergic asthmaClinical and Experimental Allergy, 2010
- Role of the Kupffer Cell in Mediating Hepatic Toxicity and CarcinogenesisToxicological Sciences, 2006
- D-Galactosamine lethality model: scope and limitationsInnate Immunity, 2004
- A Potent and Selective Histamine H4Receptor Antagonist with Anti-Inflammatory PropertiesJournal of Pharmacology and Experimental Therapeutics, 2004
- Involvement of tumor necrosis factor-α in development of hepatic injury in galactosamine-sensitized miceHepatology, 1990