Ligands
The ligands for GPR84 suggest also a relationship between inflammation and fatty acid sensing or regulation. Medium-chain free fatty acid (FFA) with carbon chain lengths of C9 to C14. Capric acid (C10:0), undecanoic acid (C11:0) and lauric acid (C12:0) are the most potent described endogeneous agonists of GPR84. Not activated by short-chain and long-chain saturated and unsaturated FFAs induced in onocytes/macrophages by LPS. In addition, the activation of GPR84 in monocytes/macrophages amplifies LPS stimulated IL-12 p40 production in a concentration dependent manner. IL-12 plays an important role in promoting cell mediated immunity to eradicate pathogens by inducing and maintaining T helper 1 responses and inhibiting T helper 2 responses. Medium chain FFAs inhibited forskolin-induced cAMP production and stimulated GTPgammaS binding in a GPR84-dependent manner. The EC50 values for medium-chain FFAs capric acid, undecanoic acid, and lauric acid at GPR84 (4, 8, and 9 mM, respectively, in the cAMP assay). These results suggest that GPR84 activation by medium-chain FFAs is coupled to a pertussis toxin-sensitive Gi/o pathway. Besides medium-chain FFAs diindolylmethane was also described as GPR84 agonist. However, the target selectivity of this molecule is also questionable because diindolylmethane is an aryl hydrocarbon receptor modulator, too. Interestingly, the patent literature mentions that besides medium chain FFAs other substances as 2,5-Dihydroxy-3-undecyl(1,4)benzoquinon, Icosa-5,8,11,14-tetraynoic acid and 5S,6R-Dihydroxy-icosa-7,9,11,14-tetraenoic acid (5S,6RdiHETE) are also ligands of GPR84. These two latest molecules say against the statement that long chain FFAs are not ligands of GPR84. Based on these results it is probable that besides medium chain FFAs some long chain FFAs can also be endogeneous ligands of GPR84. Further work is needed to confirm this hypothesis.
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