scholarly journals Rabies Virus Stimulates Nitric Oxide Production and CXC Chemokine Ligand 10 Expression in Macrophages through Activation of Extracellular Signal-Regulated Kinases 1 and 2

2004 ◽  
Vol 78 (17) ◽  
pp. 9376-9388 ◽  
Author(s):  
Kazuo Nakamichi ◽  
Satoshi Inoue ◽  
Tomohiko Takasaki ◽  
Kinjiro Morimoto ◽  
Ichiro Kurane
Keyword(s):  
Nitric Oxide ◽  
Rabies Virus ◽  
Expression Profiles ◽  
Mitogen Activated Protein Kinase ◽  
Proinflammatory Mediators ◽  
Cytokines And Chemokines ◽  
Extracellular Signal ◽  
Cxc Chemokine ◽  
Mitogen Activated Protein ◽  
Chemokine Ligand

ABSTRACT Macrophages represent an essential part of innate immunity, and the viral infection of macrophages results in the release of multiple proinflammatory mediators, such as nitric oxide (NO), cytokines, and chemokines. This study was undertaken to define the molecular mechanism of macrophage activation in response to rabies virus (RV) infection. In RAW264 murine macrophage cells, a well-characterized macrophage model, RV replication was strictly restricted, whereas cell proliferation was significantly enhanced upon RV inoculation. Transcriptional analyses for the expression of inducible forms of NO synthase (iNOS), cytokines, and chemokines revealed that RV virions potentiate the gene expression of iNOS and CXC chemokine ligand 10 (CXCL10), a major chemoattractant of T helper cell type 1. However, RV stimulation had little or no effect on the expression profiles of proinflammatory cytokines and other types of chemokines. In macrophages stimulated with UV-inactivated RV virions, as well as infectious viruses, the phosphorylation of extracellular signal-regulated kinase (ERK) 1 and 2, members of the mitogen-activated protein kinase family, was significantly induced. Specific inhibitors of MAPK/ERK kinase reduced the RV-induced production of NO and CXCL10. Furthermore, the RV-induced activation of the ERK1/2 pathway was severely impaired by the neutralization of the endosomal and lysosomal pH environment with lysosomotropic agents, indicating that endocytosis is a key step leading to the activation of ERK1/2 signaling. Taken together, these results suggest that the ERK1/2-mediated signaling pathway plays a cardinal role in the selective activation of macrophages in response to RV virions, thereby regulating cellular functions during virus infection.

scholarly journals Rabies Virus-Induced Activation of Mitogen-Activated Protein Kinase and NF-κB Signaling Pathways Regulates Expression of CXC and CC Chemokine Ligands in Microglia

2005 ◽  
Vol 79 (18) ◽  
pp. 11801-11812 ◽  
Author(s):  
Kazuo Nakamichi ◽  
Megumi Saiki ◽  
Makoto Sawada ◽  
Mutsuyo Takayama-Ito ◽  
Yutaka Yamamuro ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Rabies Virus ◽  
Expression Profiles ◽  
Nuclear Factor Κb ◽  
Brain Parenchyma ◽  
Mitogen Activated Protein Kinase ◽  
Cc Chemokine ◽  
Mitogen Activated Protein ◽  
Chemokine Ligand ◽  
Peripheral Leukocytes

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 κB (NF-κB). RV-induced expression of CXCL10 and CCL5 was achieved by the activation of p38 and NF-κB 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-κB 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.

Potentiation of nitric oxide-induced apoptosis in p53−/− vascular smooth muscle cells

2002 ◽  
Vol 282 (3) ◽  
pp. C625-C634 ◽  
Author(s):  
Melina R Kibbe ◽  
Jianrong Li ◽  
Suhua Nie ◽  
Byung Min Choi ◽  
Imre Kovesdi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Protein Kinase ◽  
Vascular Smooth Muscle ◽  
P38 Mapk ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Pathways ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Induced Apoptosis

The functional role of p53 in nitric oxide (NO)-mediated vascular smooth muscle cell (VSMC) apoptosis remains unknown. In this study, VSMC from p53−/− and p53+/+ murine aortas were exposed to exogenous or endogenous sources of NO. Unexpectedly, p53−/− VSMC were much more sensitive to the proapoptotic effects of NO than were p53+/+ VSMC. Furthermore, this paradox appeared to be specific to NO, because other proapoptotic agents did not demonstrate this differential effect on p53−/− cells. NO-induced apoptosis in p53−/− VSMC occurred independently of cGMP generation. However, mitogen-activated protein kinase (MAPK) pathways appeared to play a significant role. Treatment of the p53−/− VSMC with S-nitroso- N-acetylpenicillamine resulted in a marked activation of p38 MAPK and, to a lesser extent, of c-Jun NH2-terminal kinase, mitogen-activated protein kinase kinase (MEK) 1/2, and p42/44 (extracellular signal-regulated kinase, ERK). Furthermore, basal activity of the MEK-p42/44 (ERK) pathway was increased in the p53+/+ VSMC. Inhibition of p38 MAPK with SB-203580 or of MEK1/2 with PD-98059 blocked NO-induced apoptosis. Therefore, p53 may protect VSMC against NO-mediated apoptosis, in part, through differential regulation of MAPK pathways.

Midazolam Inhibits Proinflammatory Mediators in the Lipopolysaccharide-activated Macrophage

2006 ◽  
Vol 105 (1) ◽  
pp. 105-110 ◽  
Author(s):  
Seon Nyo Kim ◽  
Soo Chang Son ◽  
Sang Mook Lee ◽  
Cuk Seong Kim ◽  
Dae Goon Yoo ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Nitric Oxide Synthase ◽  
Inducible Nitric Oxide Synthase ◽  
Mitogen Activated Protein Kinase ◽  
Proinflammatory Mediators ◽  
Mitogen Activated Protein ◽  
Nf Kappab ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

Background Midazolam, a benzodiazepine, has a hypnotic effect and is widely used as a sedative. The role of midazolam in activation of macrophages during sepsis is not known. The aim of this study was to evaluate the antiinflammatory actions of midazolam in cultured macrophages. Methods Using a macrophage cell line, RAW264.7 cells, the effect of midazolam on proinflammatory mediators and activation of mitogen-activated protein kinase was measured by Western blot. Nuclear factor-kappaB (NF-kappaB) activation and translocation of p65 subunit of NF-kappaB was measured using luciferase assay and immunocytochemistry. Superoxide production was measured by lucigenin chemiluminescence. Results Midazolam significantly inhibited lipopolysaccharide-induced up-regulation of both cyclooxygenase 2 and inducible nitric oxide synthase in a dose-dependent manner (approximately 3-30 microm). IkappaB-alpha degradation and NF-kappaB transcriptional activity induced by lipopolysaccharide were also suppressed by the midazolam. Nuclear translocation of the p65 subunit of NF-kappaB was inhibited by midazolam. Furthermore, midazolam suppressed phosphorylation of p38 mitogen-activated protein kinase and also inhibited lipopolysaccharide-induced superoxide production in macrophages. Conclusions These results suggest that midazolam has an antiinflammatory action by inhibiting inducible nitric oxide synthase and cyclooxygenase-2 expression, possibly through suppression of NF-kappaB and p38 mitogen-activated protein kinase activation.

Sign in / Sign up

Export Citation Format

Share Document