title: GITR-GITRL system, a novel player in shock and inflammation.
abstract: Glucocorticoid-induced TNFR-Related (GITR) protein is a member of the tumor necrosis factor receptor superfamily that modulates acquired and natural immune response. It is expressed in several cells and tissues, including T cells, natural killer cells, and, at lower levels, in cells of innate immunity. GITR is activated by its ligand, GITRL, mainly expressed on antigen presenting and endothelial cells. Recent evidence suggests that the GITR/GITRL system participates in the development of inflammatory responses, including shock, either due to early response of neutrophils and macrophages, or together with autoimmune/allergic pathogenesis. The pro-inflammatory role of the GITR/GITRL system is due to: 1) modulation of the extravasation process, 2) activation of innate immunity cells, 3) activation of effector T cells also favored by partial inhibition of suppressor T cells and modulation of dendritic function. This review summarizes the in vivo role of the GITR/GITRL system in inflammation and shock, explaining the mechanisms responsible for their effects, considering the interplay among the different cells of the immune system and transduction pathways activated by GITR and GITRL triggering. The hidden aspects about GITR/GITRL function, crucial for treatment planning of inflammatory diseases and shock by modulation of this system is stressed.
authors.affiliation: Dipartimento di Medicina Clinica e Sperimentale, Sezione di Farmacologia, Tossicologia e Chemioterapia, Università di Perugia, Perugia, Italy.
authors.forename: Ludovic Tibor
authors.initials: LT
authors.lastname: Krausz
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Bianchini
authors.forename: Simona
authors.initials: S
authors.lastname: Ronchetti
authors.forename: Katia
authors.initials: K
authors.lastname: Fettucciari
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Nocentini
authors.forename: Carlo
authors.initials: C
authors.lastname: Riccardi
mesh_terms: D000818:Animals; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D012769:Shock / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: D053450:Glucocorticoid-Induced TNFR-Related Protein; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor