Haptoglobin is synthesized during granulocyte differentiation, stored in specific granules, and released by neutrophils in response to activation.
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 (beta-chain 45-65 kDa) synthesized in neutrophil precursors and stored in specific granules and a small amount of Hp (beta-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/EBPepsilon) 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.
Granulocyte Research Laboratory/Department of Hematology, Rigshospitalet, the Laboratory for Gene Therapy Research/Department of Clinical Biochemistry, University of Copenhagen, Copenhagen-Ø, Denmark.
Kim
K
Theilgaard-Mönch
Lars C
LC
Jacobsen
Marianne J
MJ
Nielsen
Thomas
T
Rasmussen
Lene
L
Udby
Maged
M
Gharib
Peter D
PD
Arkwright
Adrian F
AF
Gombart
Jero
J
Calafat
Søren K
SK
Moestrup
Bo T
BT
Porse
Niels
N
Borregaard
D002454:Cell Differentiation / Q000276:immunology*; D003594:Cytoplasmic Granules / Q000276:immunology* / Q000473:pathology; D020869:Gene Expression Profiling; D006098:Granulocytes / Q000276:immunology* / Q000473:pathology; D006242:Haptoglobins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D007153:Immunologic Deficiency Syndromes / Q000276:immunology* / Q000473:pathology; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D006242:Haptoglobins