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


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.
Okura
Hanayuki
H
Department of Somatic Stem Cell Therapy, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation, Kobe 650-0047, Japan.
Yamashita
Shizuya
S
Ohama
Tohru
T
Saga
Ayami
A
Yamamoto-Kakuta
Aya
A
Hamada
Yoko
Y
Sougawa
Nagako
N
Ohyama
Reiko
R
Sawa
Yoshiki
Y
Matsuyama
Akifumi
A
D000893:Anti-Inflammatory Agents; D016632:Apolipoprotein A-I / Q000378:metabolism* / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000737:chemistry; D006801:Humans; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000378:metabolism*; D008075:Lipoproteins, HDL; D008264:Macrophages / Q000378:metabolism; D019899:Paracrine Communication; D000077153:Progranulins; D011485:Protein Binding
D000893:Anti-Inflammatory Agents; D016632:Apolipoprotein A-I; D017077:Culture Media, Conditioned; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; D008075:Lipoproteins, HDL; D000077153:Progranulins