title: Rabies virus-induced activation of mitogen-activated protein kinase and NF-kappaB signaling pathways regulates expression of CXC and CC chemokine ligands in microglia.
abstract: Following virus infection of the central nervous system, microglia, the ontogenetic and functional equivalents of macrophages in somatic tissues, act as sources of chemokines, thereby recruiting peripheral leukocytes into the brain parenchyma. In the present study, we have systemically examined the growth characteristics of rabies virus (RV) in microglia and the activation of cellular signaling pathways leading to chemokine expression upon RV infection. In RV-inoculated microglia, the synthesis of the viral genome and the production of virus progenies were significantly impaired, while the expression of viral proteins was observed. Transcriptional analyses of the expression profiles of chemokine genes revealed that RV infection, but not exposure to inactivated virions, strongly induces the expression of CXC chemokine ligand 10 (CXCL10) and CC chemokine ligand 5 (CCL5) in microglia. RV infection triggered the activation of signaling pathways mediated by mitogen-activated protein kinases, including p38, extracellular signal-regulated kinases 1 and 2 (ERK1/2), and c-Jun N-terminal kinase, and nuclear factor kappaB (NF-kappaB). RV-induced expression of CXCL10 and CCL5 was achieved by the activation of p38 and NF-kappaB pathways. In contrast, the activation of ERK1/2 was found to down-regulate CCL5 expression in RV-infected microglia, despite the fact that it was involved in partial induction of CXCL10 expression. Furthermore, NF-kappaB signaling upon RV infection was augmented via a p38-mediated mechanism. Taken together, these results indicate that the strong induction of CXCL10 and CCL5 expression in microglia is precisely regulated by the activation of multiple signaling pathways through the recognition of RV infection.
authors.affiliation: Department of Virology 1, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nakamichi
authors.forename: Megumi
authors.initials: M
authors.lastname: Saiki
authors.forename: Makoto
authors.initials: M
authors.lastname: Sawada
authors.forename: Mutsuyo
authors.initials: M
authors.lastname: Takayama-Ito
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yamamuro
authors.forename: Kinjiro
authors.initials: K
authors.lastname: Morimoto
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kurane
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D019742:Chemokines, CC / Q000235:genetics*; D019743:Chemokines, CXC / Q000235:genetics*; D004279:DNA, Viral / Q000235:genetics; D005786:Gene Expression Regulation; D020672:I-kappa B Proteins / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D017628:Microglia / Q000276:immunology / Q000378:metabolism* / Q000821:virology*; D008954:Models, Biological; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D011818:Rabies / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000821:virology; D011820:Rabies virus / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D015398:Signal Transduction; D014779:Virus Replication
chemical_list: C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D019742:Chemokines, CC; D019743:Chemokines, CXC; C485433:Cxcl10 protein, mouse; D004279:DNA, Viral; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha