title: TLR3-mediated signal induces proinflammatory cytokine and chemokine gene expression in astrocytes: differential signaling mechanisms of TLR3-induced IP-10 and IL-8 gene expression.
abstract: Viral infection is one of the leading causes of brain encephalitis and meningitis. Recently, it was reported that Toll-like receptor-3 (TLR3) induces a double-stranded RNA (dsRNA)-mediated inflammatory signal in the cells of the innate immune system, and studies suggested that dsRNA may induce inflammation in the central nervous system (CNS) by activating the CNS-resident glial cells. To explore further the connection between dsRNA and inflammation in the CNS, we have studied the effects of dsRNA stimulation in astrocytes. Our results show that the injection of polyinosinic-polycytidylic acid (poly(I:C)), a synthetic dsRNA, into the striatum of the mouse brain induces the activation of astrocytes and the expression of TNF-alpha, IFN-beta, and IP-10. Stimulation with poly(I:C) also induces the expression of these proinflammatory genes in primary astrocytes and in CRT-MG, a human astrocyte cell line. Furthermore, our studies on the intracellular signaling pathways reveal that poly(I:C) stimulation activates IkappaB kinase (IKK), extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) in CRT-MG. Pharmacological inhibitors of nuclear factor-kappaB (NF-kappaB), JNK, ERK, glycogen synthase kinase-3beta (GSK-3beta), and dsRNA-activated protein kinase (PKR) inhibit the expression of IL-8 and IP-10 in astrocytes, indicating that the activation of these signaling molecules is required for the TLR3-mediated chemokine gene induction. Interestingly, the inhibition of PI3 kinase suppressed the expression of IP-10, but upregulated the expression of IL-8, suggesting differential roles for PI3 kinase, depending on the target genes. These data suggest that the TLR3 expressed on astrocytes may initiate an inflammatory response upon viral infection in the CNS.
authors.affiliation: Program in Cellular and Molecular Neuroscience and Department of Oral Physiology, College of Dentistry,Seoul National University, Seoul, South Korea.
authors.forename: Chanhee
authors.initials: C
authors.lastname: Park
authors.forename: Soojin
authors.initials: S
authors.lastname: Lee
authors.forename: Ik-Hyun
authors.initials: IH
authors.lastname: Cho
authors.forename: Hyun Kyoung
authors.initials: HK
authors.lastname: Lee
authors.forename: Donghoon
authors.initials: D
authors.lastname: Kim
authors.forename: Se-Young
authors.initials: SY
authors.lastname: Choi
authors.forename: Seog Bae
authors.initials: SB
authors.lastname: Oh
authors.forename: Kyungpyo
authors.initials: K
authors.lastname: Park
authors.forename: Joong Soo
authors.initials: JS
authors.lastname: Kim
authors.forename: Sung Joong
authors.initials: SJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D018925:Chemokines / Q000096:biosynthesis* / Q000235:genetics*; D019743:Chemokines, CXC / Q000096:biosynthesis* / Q000235:genetics*; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000096:biosynthesis; D000071679:Glycogen Synthase Kinase 3 beta; D020672:I-kappa B Proteins / Q000096:biosynthesis / Q000235:genetics; D007150:Immunohistochemistry; D007267:Injections; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017072:Neostriatum; D023282:Nuclease Protection Assays; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D051196:Toll-Like Receptor 3 / Q000502:physiology*; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D054357:Chemokine CXCL10; D018925:Chemokines; D019743:Chemokines, CXC; D016207:Cytokines; D020672:I-kappa B Proteins; D016209:Interleukin-8; D051196:Toll-Like Receptor 3; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D019892:eIF-2 Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D011070:Poly I-C