Antagonism of the histamine H(4) receptor reduces LPS-induced TNF production in vivo

OBJECTIVE: Antagonism of the histamine H(4) receptor (H(4)R) 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. MATERIALS AND METHODS: Wild-type and H(4)R deficient BALB/c mice received an i.p. injection of LPS in PBS in conjunction with p.o. JNJ 7777120 or JNJ 28307474 (H(4)R antagonists). Two hours later blood was collected and TNF was measured. RESULTS: Two different H(4)R antagonists inhibited LPS-induced TNF production in mice and this production was also reduced in H(4)R-deficient mice. The TNF mRNA analysis showed that the major source of the cytokine was the liver and not blood, and that the H(4)R antagonist only reduced the expression levels in the liver. Depletion or inactivation of macrophages reduced the TNF levels and eliminated the H(4)R sensitivity. Treatment with an H(4)R antagonist also reduced LPS-induced liver injury and blocked LPS-enhanced lung inflammation in mice. CONCLUSION: The data support an interaction between H(4)R and TLR activation in vivo that can drive inflammatory responses. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00011-013-0612-5) contains supplementary material, which is available to authorized users.