title: Synergistic induction of CXCL10 by interferon-gamma and lymphotoxin-alpha in astrocytes: Possible role in cerebral malaria.
abstract: Cerebral malaria (CM) has a high mortality rate and incidence of neurological sequelae in survivors. Hypoxia and cytokine expression in the brain are two mechanisms thought to contribute to the pathogenesis of CM. The cytokines interferon (IFN)-γ and lymphotoxin (LT)-α and the chemokine CXCL10 are essential for the development of CM in a mouse model. Furthermore, serum IFN-γ protein levels are higher in human CM than in controls, and CXCL10 is elevated in both serum and cerebrospinal fluid in Ghanaian paediatric CM cases. Astrocytes actively participate in CNS pathologies, becoming activated in response to various stimuli including cytokines. Astrocyte activation also occurs in murine and human CM. We here determined the responsiveness of mouse and human astrocytes to IFN-γ and LT-α, with the aim of further elucidating the role of astrocytes in CM pathogenesis. Initially we confirmed that Ifn-γ and Cxcl10 are expressed in the brain in murine CM, and that the increased Cxcl10 expression is IFN-γ-dependant. IFN-γ induced CXCL10 production in human and murine astrocytes in vitro. The degree of induction was increased synergistically in the presence of LT-α. IFN-γ induced the expression of receptors for LT-α, while LT-α increased the expression of the receptor for IFN-γ, in the astrocytes. This cross-induction may explain the synergistic effect of the two cytokines on CXCL10 production. Expression of these receptors also was upregulated in the brain in murine CM. The results suggest that astrocytes contribute to CM pathogenesis by producing CXCL10 in response to IFN-γ and LT-α.
authors.affiliation: Molecular Immunopathology Unit, Discipline of Pathology, School of Medical Sciences and Bosch Institute, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia. Electronic address: sbak7274@uni.sydney.edu.au.
authors.forename: Supun M
authors.initials: SM
authors.lastname: Bakmiwewa
authors.affiliation: Molecular Immunopathology Unit, Discipline of Pathology, School of Medical Sciences and Bosch Institute, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia. Electronic address: silviaweiser@gmx.de.
authors.forename: Silvia
authors.initials: S
authors.lastname: Weiser
authors.affiliation: Molecular Immunopathology Unit, Discipline of Pathology, School of Medical Sciences and Bosch Institute, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia. Electronic address: Meredith.lorna@gmail.com.
authors.forename: Meredith
authors.initials: M
authors.lastname: Grey
authors.affiliation: The Australian School of Advanced Medicine, Macquarie University, Sydney, NSW 2109, Australia. Electronic address: benjamin.heng@mq.edu.au.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Heng
authors.affiliation: The Australian School of Advanced Medicine, Macquarie University, Sydney, NSW 2109, Australia. Electronic address: gilles.guillemin@mq.edu.au.
authors.forename: Gilles J
authors.initials: GJ
authors.lastname: Guillemin
authors.affiliation: Molecular Immunopathology Unit, Discipline of Pathology, School of Medical Sciences and Bosch Institute, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia. Electronic address: helen.ball@sydney.edu.au.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Ball
authors.affiliation: Molecular Immunopathology Unit, Discipline of Pathology, School of Medical Sciences and Bosch Institute, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia. Electronic address: nicholas.hunt@sydney.edu.au.
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Hunt
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology*; D001921:Brain / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000235:genetics* / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D005869:Ghana; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology*; D008233:Lymphotoxin-alpha / Q000276:immunology*; D016779:Malaria, Cerebral / Q000209:etiology / Q000276:immunology*; D051379:Mice; D050794:STAT1 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D054357:Chemokine CXCL10; D016207:Cytokines; D008233:Lymphotoxin-alpha; D050794:STAT1 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: Astrocytes; CXCL10; Cerebral malaria; Interferon-gamma; Lymphotoxin-alpha