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


METHODS
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).


METHODS
Cells were treated with chenodeoxycholic acid (CDCA) and related bile acids in a 0-400 micromolar range.


METHODS
Cell viability, chemotaxis and calcium flux analysis were preformed.


RESULTS
We observed that pathophysiological levels (< or = 150 micromolar) of CDCA competitively inhibited 3H-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.
Chen
X
X
Laboratory of Molecular Immunoregulation, National Cancer Institute-Frederick Cancer Research and Development Center, Maryland 21702-1201, USA.
Yang
D
D
Shen
W
W
Dong
H F
HF
Wang
J M
JM
Oppenheim
J J
JJ
Howard
M Z
MZ
D002118:Calcium / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D002635:Chenodeoxycholic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007202:Indicators and Reagents; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D044067:Receptors, Lipoxin; D018000:Receptors, Peptide / Q000037:antagonists & inhibitors*
C105101:FPR2 protein, human; D007202:Indicators and Reagents; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic; D044067:Receptors, Lipoxin; D018000:Receptors, Peptide; D002635:Chenodeoxycholic Acid; D019204:GTP-Binding Proteins; D002118:Calcium