Tumor necrosis factor-alpha -mediated protein kinases in regulation of scavenger receptor and foam cell formation on macrophage.
We previously reported tumor necrosis factor-alpha (TNF) modulates transcriptional and post-transcriptional down-regulation of macrophage scavenger receptor (MSR) (Hsu, H. Y., Nicholson, A. C., and Hajjar, D. P. (1996) J. Biol. Chem. 271, 7767-7773); however, TNF-mediated signaling mechanisms are unknown. Here, we demonstrate that ligation of TNF receptor stimulates activity of p21-activated protein kinase (PAK) and mitogen-activated protein kinases (MAPK) as follows: ERK, JNK, and p38 in murine macrophage J774A.1 cells. Upon activation of protein kinases (PK), TNF rapidly increases MSR message and protein; later it markedly reduces MSR expression. Studies using PK inhibitors and dominant negative constructs demonstrate phosphatidylinositol 3-kinase/Rac1/PAK/JNK and phosphatidylinositol 3-kinase/Rac1/PAK/p38 pathways contribute to important roles in the late stage of TNF down-regulation of MSR expression and taking up of OxLDL. Alternatively, the PKC/MEK1/ERK pathway in the early stage plays a significant role in up-regulation of the MSR gene. By using anti-TNF-R1 agonist antibody, we further confirm TNF-R1-mediated MAPK in regulation of MSR. Furthermore, in MSR gene promoter-driven luciferase reporter assays with TNF, PKC activator increases, but antioxidant N-acetylcysteine, PK inhibitors, and dominant negative constructs decrease luciferase activity in MSR gene promoter-transfected cells. Our current results show the first evidence of crucial roles for TNF-mediated MAPK pathways in the transcriptional regulation of MSR gene and increase MSR expression; in contrast, with TNF longer treatment the pathways down-regulate MSR and foam cell formation probably via post-transcriptional process.
Hsu
H Y
HY
Faculty of Medical Technology, Institute of Biotechnology in Medicine, National Yang-Ming University, 112 Taipei, Taiwan.
Twu
Y C
YC
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D005487:Foam Cells / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases; D008077:Lipoproteins, LDL / Q000378:metabolism; D048670:MAP Kinase Kinase 4; D008264:Macrophages / Q000737:chemistry / Q000502:physiology*; D008565:Membrane Proteins; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D017382:Reactive Oxygen Species; D011971:Receptors, Immunologic / Q000235:genetics* / Q000502:physiology; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D013482:Superoxide Dismutase / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases
D000730:Androstadienes; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein; D013482:Superoxide Dismutase; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D000077191:Wortmannin