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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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PHAGOCYTES
Haptoglobin is synthesized during granulocyte differentiation, stored in specific granules, and released by neutrophils in response to activation
Kim Theilgaard-Mönch,
Lars C. Jacobsen,
Marianne J. Nielsen,
Thomas Rasmussen,
Lene Udby,
Maged Gharib,
Peter D. Arkwright,
Adrian F. Gombart,
Jero Calafat,
Søren K. Moestrup,
Bo T. Porse, and
Niels Borregaard
From the Granulocyte Research Laboratory/Department of Hematology, Rigshospitalet, the Laboratory for Gene Therapy Research/Department of Clinical Biochemistry, Rigshospitalet, the Department of Hematology/Herlev Hospital, and the 8th Rigshospitalet, University of Copenhagen, Copenhagen Denmark; the Department of Medical Biochemistry, University of Aarhus, Aarhus, Denmark; the Department of Hematology, Royal Manchester Children's Hospital, Manchester, United Kingdom; Booth Hall Children's Hospital, University of Manchester, Manchester, United Kingdom; the Division of Hematology/Oncology, Cedars-Sinai Medical Center, Burns and Allan Research Institute, David Geffen School of Medicine at University of California, Los Angeles (UCLA); and the Department of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Haptoglobin (Hp) is a plasma protein synthesized primarily by hepatocytes. It exerts a broad range of anti-inflammatory activities and acts indirectly as a bacteriostatic agent and an antioxidant by virtue of its ability to bind free hemoglobin (Hb) and to 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 specific granule deficiency (SGD) lacked neutrophil-derived Hp. Neutrophils contained a large amount of highly glycosylated Hp ( -chain 45-65 kDa) synthesized in neutrophil precursors and stored in specific granules and 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 is released by neutrophils in response to activation. Hence, neutrophil-derived Hp might reduce tissue damage and bacterial growth at sites of infection or injury by propagating anti-inflammatory activities and Hb clearance. (Blood. 2006;108:353-361)
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