Characterization of chenodeoxycholic acid as an endogenous antagonist of the G-coupled formyl peptide receptors

Objective and design: To demonstrate the role of bile acids in immune modulation we examined the ability of select bile acids to inhibit leukocyte migration and chemoattractant receptor function. Materials: To elucidate this mechanism, we employed primary human monocytes, neutrophils and cell lines transfected to express either the high affinity fMLP receptor (FPR) or the low affinity fMLP receptor like 1 (FPRL1). Treatment: Cells were treated with chenodeoxycholic acid (CDCA) and related bile acids in a 0-400 micromolar range. Method: Cell viability, chemotaxis and calcium flux analysis were preformed. Results: We observed that pathophysiological levels (less than or equal to 150 micromolar) of CDCA competitively inhibited H-3-fMLP binding to human monocytes, FPR and FPRL1 transfected cells. Additionally, CDCA reduced both the chemotactic and calcium flux responses induced by fMLP or "W" peptide. Further, CDCA inhibited anti-FPR antibody binding to monocytes. Conclusions: CDCA selectively inhibited human leukocyte chemotaxis and calcium flux induced by fMLP, but not other chemoattractants, suggesting a mechanism for inhibition of inflammation and suppression of innate immune response.