Involvement of growth differentiation factor-15/macrophage inhibitory cytokine-1 (GDF-15/MIC-1) in oxLDL-induced apoptosis of human macrophages in vitro and in arteriosclerotic lesions.
Growth differentiation factor-15/macrophage inhibitory cytokine-1 (GDF-15/MIC-1) is a new member of the transforming growth factor beta (TGF-beta) superfamily, which has most recently been found in activated macrophages (MPhi). We have now investigated GDF-15/MIC-1 in human MPhi after exposure to oxidized low-density lipoproteins (oxLDL) related mediators in vitro and in arteriosclerotic carotid arteries. Using RT-PCR and Western blotting a pronounced induction of GDF-15/MIC-1 expression by oxLDL, C6-ceramide, tumor necrosis factor (TNFalpha) and hydrogen peroxide (H2O2) was found in cultured human MPhi. In 11 human arteriosclerotic carotid arteries, immunohistochemical analyses supported by computer-assisted morphometry and regression analyses demonstrated a significant colocalization of GDF-15/MIC-1 immunoreactivity (IR) with oxLDL IR and manganese superoxide dismutase (MnSOD) IR in CD68 immunoreactive (ir) MPhi, which were also expressing AIF-IR (apoptosis-inducing factor), caspase-3-IR (CPP32), PARP-IR, c-Jun/AP-1-IR and p53-IR. Our data suggest that GDF-15/MIC-1 is inducible in human MPhi by oxLDL and its mediators in vitro and is supposed to contribute to oxidative stress dependent consequences in arteriosclerotic plaques, e.g. modulating apoptosis and inflammatory processes in activated MPhi.
Department of Anatomy and Cell Biology III, Interdisciplinary Center of Neurosciences (IZN), University of Heidelberg, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany.
Daniel
D
Schlittenhardt
Andreas
A
Schober
Jens
J
Strelau
Gabriel A
GA
Bonaterra
Walther
W
Schmiedt
Klaus
K
Unsicker
Jürgen
J
Metz
Ralf
R
Kinscherf
D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis* / Q000235:genetics; D002339:Carotid Arteries / Q000378:metabolism; D002340:Carotid Artery Diseases / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D002518:Ceramides / Q000494:pharmacology; D024161:Collagen Type XI / Q000378:metabolism; D005420:Flavoproteins / Q000378:metabolism; D055436:Growth Differentiation Factor 15; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007091:Image Processing, Computer-Assisted / Q000379:methods; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D051033:Apoptosis Inducing Factor; D019485:Bone Morphogenetic Proteins; D053148:Caspase 3; D020169:Caspases; D002518:Ceramides; D024161:Collagen Type XI; D005420:Flavoproteins; D055436:Growth Differentiation Factor 15; D006861:Hydrogen Peroxide; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D013482:Superoxide Dismutase; D014409:Tumor Necrosis Factor-alpha; C494829:AIFM1 protein, human; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C499319:COL11A2 protein, human; C526140:GDF15 protein, human; C099252:oxidized low density lipoprotein; C101954:N-caproylsphingosine; C499320:PARP1 protein, human; C505407:CASP3 protein, human