title: Downregulation of transforming growth factor-beta2 facilitates inflammation in the central nervous system by reciprocal astrocyte/microglia interactions.
abstract: The central nervous system is an immune privileged organ in which inflammatory reactions are normally downregulated by mechanisms that are not completely understood. Transforming growth factor (TGF)-beta2 is constitutively expressed in the adult central nervous system and little is known about its regulation and modulatory role during neuroinflammation. In this study, we show that TGFbeta2 mRNA and protein are downregulated in the acute phase of chronic relapsing experimental autoimmune encephalomyelitis, whereas the homologous cytokine TGFbeta1 is upregulated. To further characterize regulatory mechanisms, we resorted to an in vitro glial cell culture system. The proinflammatory cytokines IFNgamma and TNFalpha suppressed TGFbeta2 secretion by astrocytes, the major intracerebral producers of TGFbeta2. On the cellular level, activated microglia inhibited TGFbeta2 secretion but induced TGFbeta1 through soluble factors. On the other hand, TGFbeta2 influenced antigen-presenting cell functions of microglia by downregulating major histocompatibility complex class II expression and costimulatory/adhesion molecules, and thereby inhibited myelin basic protein-specific T cell proliferation. These data suggest that TGFbeta2 plays a central role in maintenance of the immune privilege of the central nervous system. Downregulation of astrocytic TGFbeta2 by T cell- and microglia-secreted cytokines appears to be a critical step in providing the grounds for acute and chronic neuroinflammation.
authors.affiliation: Department of Neurology, University of Wurzburg, Wurzburg, Germany.
authors.forename: Ines
authors.initials: I
authors.lastname: Siglienti
authors.forename: Andrew
authors.initials: A
authors.lastname: Chan
authors.forename: Christoph
authors.initials: C
authors.lastname: Kleinschnitz
authors.forename: Sebastian
authors.initials: S
authors.lastname: Jander
authors.forename: Klaus V
authors.initials: KV
authors.lastname: Toyka
authors.forename: Ralf
authors.initials: R
authors.lastname: Gold
authors.forename: Guido
authors.initials: G
authors.lastname: Stoll
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000737:chemistry / Q000502:physiology*; D002452:Cell Count / Q000379:methods; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism* / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D016898:Interferon-alpha / Q000494:pharmacology; D017628:Microglia / Q000737:chemistry / Q000502:physiology*; D004676:Myelin Basic Protein / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D053781:Transforming Growth Factor beta2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D005904:Glial Fibrillary Acidic Protein; D000949:Histocompatibility Antigens Class II; D016898:Interferon-alpha; D004676:Myelin Basic Protein; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2