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PNAS 105 (46): 17949-17954

Copyright © 2008 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / MEDICAL SCIENCES

Tonic inhibition of chemotaxis in human plasma

Stephen E. Malawistaa,1, Anne de Boisfleury Chevanceb, Jo van Dammec, and Charles N. Serhand

aDepartment of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520; bCentre d'Ecologie Cellulaire, Hôpital de la Salpétrière, 75013 Paris, France; cRega Institute for Medical Research, University of Leuven, Leuven 3000, Belgium; and dCenter for Experimental Therapeutics and Reperfusion Injury, Department of Anaesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115

Edited by Charles A. Dinarello, University of Colorado Health Sciences Center, Denver, CO, and approved September 18, 2008

Received for publication March 14, 2008.

Abstract: We found exaggerated chemotaxis in plasma treated with EDTA and thought that the EDTA might itself be inhibiting a tonic inhibitor(s) of chemotaxis. Our plasma fractionations suggested that evidence should be sought for a lipid moiety carrying this activity, and on spectrometry (LC-MS-MS together with GC-MS analyses), the biologically active but not the inactive fraction contained oleic and arachidonic acids. Because fatty acids are largely protein bound, we flooded plasma preparations with delipidated albumin, reasoning that it would bind enough fatty acids, including inhibitory ones, to counter their tonic inhibition. Indeed, we observed dramatic increases in chemotaxis. Hence, adding delipidated albumin to plasma has a similar effect to that of adding EDTA—amplification of the chemotactic response. Oleic acid in physiologic concentrations diminishes the magnifying effects of both EDTA and of delipidated albumin, and in fact diminishes the chemotactic response even without the presence of the amplifiers of chemotaxis. In contrast, arachidonic acid amplifies further the effect of EDTA but not of delipidated albumin, and this augmentation appears to be caused by an EDTA-dependent enrichment of the chemotactic gradient with leukotriene B4 (LTB4). We conclude that oleic acid, the blood levels of which vary among individuals, is at least one tonic inhibitor of chemotaxis in plasma.

Key Words: fatty acids • oleic acid • neutrophils

Author contributions: S.E.M., J.v.D., and C.N.S. designed research; S.E.M., A.d.B.C., J.v.D., and C.N.S. performed research; S.E.M. and A.d.B.C. contributed new reagents/analytic tools; S.E.M., A.d.B.C., J.v.D., and C.N.S. analyzed data; and S.E.M. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0802572105/DCSupplemental.

1To whom correspondence should be addressed at: Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520. E-mail: stephen.malawista{at}yale.edu

© 2008 by The National Academy of Sciences of the USA

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