Antagonism of the histamine H^sub 4^ receptor reduces LPS-induced TNF production in vivo

Antagonism of the histamine H^sub 4^ receptor (H^sub 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. Wild-type and H^sub 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^sub 4^R antagonists). Two hours later blood was collected and TNF was measured. Two different H^sub 4^R antagonists inhibited LPS-induced TNF production in mice and this production was also reduced in H^sub 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^sub 4^R antagonist only reduced the expression levels in the liver. Depletion or inactivation of macrophages reduced the TNF levels and eliminated the H^sub 4^R sensitivity. Treatment with an H^sub 4^R antagonist also reduced LPS-induced liver injury and blocked LPS-enhanced lung inflammation in mice. The data support an interaction between H^sub 4^R and TLR activation in vivo that can drive inflammatory responses.[PUBLICATION ABSTRACT]