Antagonism of the histamine H4 receptor reduces LPS-induced TNF production in vivo

作者：Cowden, Jeffery M.; Yu, Fuqu; Challapalli, Mamatha; Huang, Jing-Feng; Kim, Sunhwa; Fung-Leung, Wai-Ping; Ma, Jing Ying; Riley, Jason P.; Zhang, Mai; Dunford, Paul J.; Thurmond, Robin L.^*

来源：Inflammation Research, 2013, 62(6): 599-607.

DOI：10.1007/s00011-013-0612-5

• Histamine
• Macrophages
• Kupffer cells
• Toll-like receptors

Antagonism of the histamine H-4 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.

• 出版日期2013-6