title: c-Jun N-terminal kinase and, to a lesser extent, p38 mitogen-activated protein kinase regulate inducible nitric oxide synthase expression in hyaluronan fragments-stimulated BV-2 microglia.
abstract: Lower molecular weight of hyaluronan (HA) fragments are capable of activating macrophages to express a number of inflammatory mediators through the interaction with the HA receptor CD44. Recent evidence has demonstrated that concomitant induction of CD44 and HA synthase 2 (HAS-2) mRNA in microglia of the ischemic brain. However, the influence of HA fragments on the activation of microglia is poorly understood. In this study, we demonstrated that HA fragments induced inducible NO synthase (iNOS) expression in BV-2 microglia in a dose-dependent manner and was synergized with interferon-gamma (IFN-gamma). Moreover, HA fragments could induce the activation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK1/ERK2), and c-Jun N-terminal kinase (JNK) in a time and dose-dependent fashion. The HA fragments-induced iNOS expression was suppressed by the selective inhibitors of JNK and, to a lesser extent, p38 MAPK. These results suggest that the induction of iNOS by HA fragments is significantly dependent on JNK than on p38 MAPK signaling pathways and support the hypothesis that HA fragments may be an important regulator in the activation of microglia at sites of ischemic brain.
authors.affiliation: Neuro-Medical Scientific Center, Buddhist Tzu-Chi General Hospital, Tzu-Chi College of Technology, Hualien 970, Taiwan, ROC.
authors.forename: Mei Jen
authors.initials: MJ
authors.lastname: Wang
authors.forename: Kee Ching G
authors.initials: KC
authors.lastname: Jeng
authors.forename: Jon Son
authors.initials: JS
authors.lastname: Kuo
authors.forename: Huan Lian
authors.initials: HL
authors.lastname: Chen
authors.forename: Hsin Yi
authors.initials: HY
authors.lastname: Huang
authors.forename: Wu Fu
authors.initials: WF
authors.lastname: Chen
authors.forename: Shinn Zong
authors.initials: SZ
authors.lastname: Lin
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006820:Hyaluronic Acid / Q000494:pharmacology* / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases; D017628:Microglia / Q000187:drug effects* / Q000201:enzymology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017207:Rats, Sprague-Dawley; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D006820:Hyaluronic Acid; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases