title: Stimulation of glucocorticoid-induced tumor necrosis factor receptor family-related protein ligand (GITRL) induces inflammatory activation of microglia in culture.
abstract: Glucocorticoid-induced tumor necrosis factor receptor family-related protein ligand (GITRL) is a member of the tumor necrosis factor superfamily (TNFSF) and is known to act as a costimulator in the immune system by binding to GITR. GITRL is expressed in endothelial cells, dendritic cells, macrophages, and B cells, but it is not known whether GITRL is expressed in brain microglia cells. Here, we investigated the expression of GITR and GITRL and their potential role in microglia cells. Using BV-2 mouse microglia cells and mouse primary microglia cultures, we have demonstrated that 1) both GITR and GITRL are expressed in microglia cells; 2) stimulation of GITRL induces inflammatory activation of microglia on the basis of production of nitric oxide (NO) and expression of inducible nitric oxide synthase, cyclooxygenase-2, CD40, and matrix metalloproteinase-9; 3) GITRL-mediated microglial NO production partially depends on p38 MAPK, JNK, and nuclear factor-kappaB pathways; and 4) GITRL stimulation also induces microglia cell death. These results indicate that GITR and GITRL are functionally expressed on brain microglia and that the stimulation of GITRL can induce inflammatory activation of microglia. The GITR/GITRL system may play an important role in neuroinflammation.
authors.affiliation: Department of Pharmacology, Brain Science and Engineering Institute, CMRI, Kyungpook National University School of Medicine, Daegu, Korea.
authors.forename: Heehong
authors.initials: H
authors.lastname: Hwang
authors.forename: Shinrye
authors.initials: S
authors.lastname: Lee
authors.forename: Won-Ha
authors.initials: WH
authors.lastname: Lee
authors.forename: Ho-Jae
authors.initials: HJ
authors.lastname: Lee
authors.forename: Kyoungho
authors.initials: K
authors.lastname: Suk
mesh_terms: D000818:Animals; D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D053450:Glucocorticoid-Induced TNFR-Related Protein; D051379:Mice; D017628:Microglia / Q000201:enzymology / Q000276:immunology* / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D048069:Tumor Necrosis Factors / Q000378:metabolism*
chemical_list: D053450:Glucocorticoid-Induced TNFR-Related Protein; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse; C478966:Tnfsf18 protein, mouse; D048069:Tumor Necrosis Factors; D009569:Nitric Oxide