HDL/apolipoprotein A-I binds to macrophage-derived progranulin and suppresses its conversion into proinflammatory granulins.

AIM HDL has anti-inflammatory effects on macrophages, although the mechanism of action remains unclear. We hypothesized that HDL suppresses the conversion of macrophage-secreted factors into proinflammatory factors via binding, and tried to identify the factor that could form a complex with HDL and/or apolipoprotein (apo) A-I. METHODS AND RESULTS In conditioned media obtained from human monocyte-derived macrophages, we found an apo A-I binding protein and identified the protein as progranulin/proepithelin/acrogranin/PCDGF. Co-immunoprecipitation analysis showing that progranulin binds and forms a complex with apo A-I and the presence of progranulin in the HDL fraction in the sera indicated that progranilin is a novel apolipoprotein. Conditioned media of HEK293 cells transfected with progranulin augmented the expression of TNF-alpha and IL-1-beta on macrophages, but these effects of progranulin were inhibited by co-incubation with HDL or apo A-I. Anti-progranulin antibodies also reduced the expression of TNF-alpha and IL-1-beta on macrophages. Granulins as conversion products derived from progranilin increased TNF-alpha and IL-1-beta expression and the effects were not suppressed by HDL. CONCLUSIONS Our results suggest that the anti-inflammatory effects of HDL on macrophages might be due to suppression of the conversion of progranulin into proinflammatory granulins by forming a complex.

[1]  C. H. Ong,et al.  Regulation of progranulin expression in myeloid cells. , 2006, American journal of physiology. Regulatory, integrative and comparative physiology.

[2]  M. Ezekowitz,et al.  High-density lipoprotein, but not low-density lipoprotein cholesterol levels influence short-term prognosis after acute coronary syndrome: results from the MIRACL trial. , 2005, European heart journal.

[3]  C. H. Ong,et al.  Progranulin (granulin-epithelin precursor, PC-cell derived growth factor, acrogranin) in proliferation and tumorigenesis. , 2003, Histology and histopathology.

[4]  K. Watson,et al.  High-density lipoprotein function recent advances. , 2005, Journal of the American College of Cardiology.

[5]  H. Brewer,et al.  HDL metabolism and the role of HDL in the treatment of high-risk patients with cardiovascular disease , 2007, Current cardiology reports.

[6]  R. Schultz,et al.  Modulation of mouse preimplantation embryo development by acrogranin (epithelin/granulin precursor). , 2000, Developmental biology.

[7]  C. H. Ong,et al.  Progranulin is a mediator of the wound response , 2003, Nature Medicine.

[8]  S. Yokoyama.  ABCA1 and biogenesis of HDL. , 2006, Journal of atherosclerosis and thrombosis.

[9]  A. Szuba,et al.  The role of chemokines in human cardiovascular pathology: enhanced biological insights. , 2002, Atherosclerosis.

[10]  S. Melquist,et al.  Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17 , 2006, Nature.

[11]  A. Bateman,et al.  Structural and functional analysis of a promoter of the human granulin/epithelin gene. , 1996, The Biochemical journal.

[12]  A. Maggioni,et al.  Variations in lipoprotein levels after myocardial infarction and unstable angina: the LATIN trial. , 2002, Italian heart journal : official journal of the Italian Federation of Cardiology.

[13]  H. Erdjument-Bromage,et al.  Conversion of Proepithelin to Epithelins Roles of SLPI and Elastase in Host Defense and Wound Repair , 2002, Cell.

[14]  S. Yamashita,et al.  Molecular biology and pathophysiological aspects of plasma cholesteryl ester transfer protein. , 2000, Biochimica et biophysica acta.

[15]  Zhiheng He,et al.  Progranulin (granulin-epithelin precursor, PC-cell-derived growth factor, acrogranin) mediates tissue repair and tumorigenesis , 2003, Journal of Molecular Medicine.

[16]  S. Kihara,et al.  Identification of a GPI-anchored type HDL-binding protein on human macrophages. , 2000, Biochemical and biophysical research communications.

[17]  K. Watanabe,et al.  Exon/intron organization of the gene encoding the mouse epithelin/granulin precursor (acrogranin) , 1993, FEBS letters.

[18]  C. Duijn,et al.  Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21 , 2006, Nature.

[19]  M. Chapman.  From pathophysiology to targeted therapy for atherothrombosis: a role for the combination of statin and aspirin in secondary prevention. , 2007, Pharmacology & therapeutics.