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* Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine and
Department of Surgery, Division of Trauma Surgery, University of Pittsburgh, Pittsburgh, PA 15213;
Department of Medicine, Division of Pulmonary and Critical Care Medicine, Harborview Medical Center and
Department of Medicine, Pulmonary Research Laboratories, VA/Puget Sound Medical Center, University of Washington, Seattle, WA;
¶ Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN; and
|| Department of Pathology, Medical College of Georgia, Augusta, GA
The Duffy blood group Ag (dfy) binds selective CXC and CC chemokines at high affinity and is expressed on erythrocytes and endothelial cells. However, it does not transmit a signal via G proteins, as occurs with other seven-transmembrane receptors. We hypothesized that dfy functions as a chemokine reservoir and regulates inflammation by altering soluble chemokine concentrations in the blood and tissue compartments. We determined whether Duffy Ag "loss-of-function" phenotypes (human and murine) are associated with alterations in plasma chemokine concentrations during the innate inflammatory response to LPS. Plasma CXCL8 and CCL2 concentrations from humans homozygous for the GATA-1 box polymorphism, a dfy polymorphism that abrogates erythrocyte chemokine binding, were higher than in heterozygotes following LPS stimulation of their whole blood in vitro. Similarly, dfy–/– mice showed higher plasma MIP-2 concentrations than dfy+/+ mice following LPS stimulation of whole blood in vitro. We then determined the relative contributions of erythrocyte and endothelial Duffy Ag in modifying chemokine concentrations and neutrophil recruitment in the lungs following intratracheal LPS administration in dfy–/– and dfy+/+ mice reconstituted with dfy–/– or dfy+/+ marrow. Mice lacking endothelial dfy expression had higher MIP-2 and keratinocyte chemoattractant concentrations in the airspaces. Mice lacking erythrocyte dfy had higher MIP-2 and keratinocyte chemoattractant concentrations in the lung tissue vascular space, but lower plasma chemokine concentrations associated with attenuated neutrophil recruitment into the airspaces. These data indicate that dfy alters soluble chemokine concentrations in blood and local tissue compartments and enhances systemic bioavailability of chemokines produced during local tissue inflammation.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants HL70178 (to J.S.L.), American Heart Associate Pacific Mountain Affiliate Beginning Grant-in-Aid (to J.S.L.), Grant HL72923 (to M.W.W.), Grant HL70840 (to G.M.-B.), and Grant P50 HL73996 (to T.R.M.).
2 Address correspondence and reprint requests to Dr. Janet S. Lee, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, NW628 MUH, 3459 Fifth Avenue, Pittsburgh, PA 15213. E-mail address: leejs3{at}upmc.edu
3 Abbreviations used in this paper: MIP-1, monocyte inflammatory protein 1; BAL, bronchoalveolar lavage; dfy, Duffy blood group Ag; KC, keratinocyte chemoattractant; MPO, myeloperoxidase; WT, wild type; KO, knockout; m, monoclonal; SNP, single nucleotide polymorphism; PMN, polymorphonuclear.
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