title: Ligands of macrophage scavenger receptor induce cytokine expression via differential modulation of protein kinase signaling pathways.
abstract: Our previous works demonstrated that ligands of macrophage scavenger receptor (MSR) induce protein kinases (PKs) including protein-tyrosine kinase (PTK) and up-regulate urokinase-type plasminogen activator expression (Hsu, H. Y., Hajjar, D. P., Khan, K. M., and Falcone, D. J. (1998) J. Biol. Chem. 273, 1240--1246). To continue to investigate MSR ligand-mediated signal transductions, we focus on ligands, oxidized low density lipoprotein (OxLDL), and fucoidan induction of the cytokines tumor necrosis factor-alpha (TNF) and interleukin 1 beta (IL-1). In brief, in murine macrophages J774A.1, OxLDL and fucoidan up-regulate TNF production; additionally, fucoidan but not OxLDL induces IL-1 secretion, prointerleukin 1 (proIL-1, precursor of IL-1) protein, and proIL-1 message. Simultaneously, fucoidan stimulates activity of interleukin 1-converting enzyme. We further investigate the molecular mechanism by which ligand binding-induced PK-mediated mitogen-activated protein kinase (MAPK) in regulation of expression of proIL-1 and IL-1. Specifically, fucoidan stimulates activity of p21-activated kinase (PAK) and of the MAPKs extracellular signal-regulated kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38. Combined with PK inhibitors and genetic mutants of Rac1 and JNK in PK activity assays, Western blotting analyses, and IL-1 enzyme-linked immunosorbent assay, the role of individual PKs in the regulation of proIL-1/IL-1 was extensively dissected. Moreover, tyrosine phosphorylation of pp60Src as well as association between pp60Src and Hsp90 play important roles in fucoidan-induced proIL-1 expression. We are the first to establish two fucoidan-mediated signaling pathways: PTK(Src)/Rac1/PAK/JNK and PTK(Src)/Rac1/PAK/p38, but not PTK/phospholipase C-gamma 1/PKC/MEK1/ERK, playing critical roles in proIL-1/IL-1 regulation. Our current results indicate and suggest a model for MSR ligands differentially modulating specific PK signal transduction pathways, which regulate atherogenesis-related inflammatory cytokines TNF and IL-1.
authors.affiliation: Faculty of Medical Technology, Institute of Biotechnology in Medicine, National Yang-Ming University, Taipei 112, Taiwan. hyhsu@ym.edu.tw
authors.forename: H Y
authors.initials: HY
authors.lastname: Hsu
authors.forename: S L
authors.initials: SL
authors.lastname: Chiu
authors.forename: M H
authors.initials: MH
authors.lastname: Wen
authors.forename: K Y
authors.initials: KY
authors.lastname: Chen
authors.forename: K F
authors.initials: KF
authors.lastname: Hua
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D015815:Cell Adhesion Molecules / Q000502:physiology; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005643:Fucose / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D007093:Imidazoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D008024:Ligands; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009025:Morpholines / Q000494:pharmacology; D010084:Oxidation-Reduction; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011134:Polysaccharides / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000502:physiology*; D051116:Receptors, Scavenger; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000730:Androstadienes; D015815:Cell Adhesion Molecules; D002867:Chromones; D016207:Cytokines; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D007375:Interleukin-1; D008024:Ligands; D008077:Lipoproteins, LDL; D009025:Morpholines; D011134:Polysaccharides; D011725:Pyridines; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein; D005643:Fucose; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C007789:fucoidan; D019869:Phosphatidylinositol 3-Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077191:Wortmannin