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Blood, 1 July 2006, Vol. 108, No. 1, pp. 353-361.
Prepublished online as a Blood First Edition Paper on March 16, 2006; DOI 10.1182/blood-2005-09-3890.
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Submitted September 29, 2005
Accepted February 15, 2006
Haptoglobin is synthesized during granulocytic differentiation, stored in specific granules, and released by neutrophils in response to activation
Kim Theilgaard-Monch, Lars C Jacobsen, Marianne J Nielsen, Thomas Rasmussen, Lene Udby, Maged Gharib, Peter D Arkwright, Adrian F Gombart, Jero Calafat, Soren K Moestrup, Bo T Porse, and Niels Borregaard*
Department of Hematology, Rigshospitalet,, The Granulocyte Research Laboratory, University of Copenhagen, Copenhagen, Denmark
University of Aarhus, Department of Medical Biochemistry, Aarhus, Denmark
Herlev Hospital, University of Copenhagen, Department of Hematology, Copenhagen, Denmark
Royal Manchester Children's Hospital, Department of Hematology, Manchester, United Kingdom
University of Manchester, Booth Hall Children's Hospital, Manchester, United Kingdom
Cedars-Sinai Medical Center, Burns and Allan Research Institute, David Geffen School of Medicine at UCLA, Division of Hematology/Oncology, Los Angeles, USA
The Netherlands Cancer Institute, Department of Cell Biology, Amsterdam, The Netherlands
Deparment of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, The Laboratory for Gene Therapy Research, Copenhagen, Denmark
* Corresponding author; email: borregaard{at}rh.dk.
Haptoglobin (Hp) is a plasma protein synthesized primarily by hepatocytes. Hp exerts a broad range of anti-inflammatory activities and acts indirectly as a bacteriostatic agent and an anti-oxidant by virtue of its ability to bind free hemoglobin (Hb), and facilitate its immediate clearance by macrophages. We identified Hp as a novel specific granule protein of neutrophils by means of immunoelectron microscopy, subcellular fractionation, and exocytosis studies. Consistent with these findings, blood cells from a patient with neutrophil-specific granule deficiency (SGD) lacked Hp. Neutrophils contain a large amount of highly glycosylated Hp ( -chain 45-65 kDA) that is synthesized in neutrophil precursors and stored in specific granules, as well as a small amount of Hp (-chain 39 kDA) endocytosed from plasma and stored in secretory vesicles. Subsequent binding studies revealed that Hp from specific granules binds to Hb. Finally, the CCAAT enhancer binding protein-epsilon (C/EBP ) induced Hp transcription in a myeloid cell line, suggesting that Hp expression in myeloid cells, as in hepatocytes, is at least partially regulated by members of the C/EBP transcription factor family.
Collectively, these findings demonstrate that Hp is stored in specific granules and released by neutrophils in response to activation. Hence, neutrophil-derived Hp might reduce tissue damage and bacterial growth at sites of infection/injury by propagating anti-inflammatory activities and clearance of Hb.
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