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.

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 Effect of Urban Particulate Matter on Vocal Fold Fibrosis through the MAPK/NF-κB Signaling Pathway

2020 ◽  
Vol 21 (18) ◽  
pp. 6643
Author(s):  
Ho-Ryun Won ◽  
Seung-Nam Jung ◽  
Min-Kyung Yeo ◽  
Shinae Yi ◽  
Lihua Liu ◽  
...  
Keyword(s):  
Particulate Matter ◽  
Signaling Pathways ◽  
Vocal Fold ◽  
Animal Experiments ◽  
Vocal Folds ◽  
Underlying Mechanism ◽  
Nuclear Factor Κb ◽  
Mitogen Activated Protein Kinase ◽  
Histological Evaluation ◽  
Mitogen Activated Protein

Particulate matter (PM) is an environmental exposure factor that adversely affects human health. PM is a risk factor for various diseases. However, the mechanism by which PM affects the vocal folds (VF) has not yet been evaluated. Thus, we investigated the cytotoxic effects of PM on human vocal fold fibroblasts (hVFF) and the underlying signaling pathways. hVFF were isolated from human VF. The effect of PM on hVFF, and the underlying mechanism, were analyzed using Western blot, quantitative real-time polymerase chain reaction, and flow cytometry. In addition, a histological evaluation was performed in animal experiments. Cell proliferation decreased after the PM treatment. PM increased the expression of interleukin (IL)-6 and IL-1β. The generation of reactive oxygen species (ROS) in PM-treated hVFF and subsequent activation of the mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways were confirmed. Furthermore, PM increased the expression of fibrosis-related markers and induced the accumulation of collagen in the extracellular matrix. As a result, PM exposure significantly enhances the inflammatory response on VF through the ROS-mediated activation of the MAPK and NF-κB signaling pathways. In addition, PM promotes differentiation into myofibroblasts and induces fibrosis. These results suggest that PM triggers an inflammatory reaction through ROS production and causes VF fibrosis.

Signaling Pathways Regulating IL-1α-induced COX-2 Expression

2007 ◽  
Vol 86 (2) ◽  
pp. 186-191 ◽  
Author(s):  
S. Ogata ◽  
Y. Kubota ◽  
T. Yamashiro ◽  
H. Takeuchi ◽  
T. Ninomiya ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mrna Expression ◽  
Signaling Pathways ◽  
Nuclear Factor Κb ◽  
Mitogen Activated Protein Kinase ◽  
Odontogenic Keratocyst ◽  
Prostaglandin E ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Cox 2

Interleukin-1α(IL-1α) stimulates the production of prostaglandin E2 (PGE2) in odontogenic keratocyst fibroblasts. However, the signaling pathways remain obscure. In this study, we investigated IL-1αsignaling pathways that regulate cyclooxygenase-2 (COX-2) expression in odontogenic keratocyst fibroblasts. IL-1αincreased the expression of COX-2 mRNA and protein, and PGE2 secretion in the fibroblasts. IL-1αincreased the phosphorylation of extracellular signal-regulated protein kinase-1/2 (ERK1/2), p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK). PD-98059, SB-203580, SP-600125, and PDTC—which are inhibitors of ERK1/2, p38, JNK, and nuclear factor-κB (NF-κB), respectively—attenuated the IL-1α-induced COX-2 mRNA expression and activated protein kinase C PGE2 secretion. IL-1α(PKC), and PKC inhibitor staurosporine inhibited IL-1α-induced phosphorylation of ERK1/2, p38, and JNK, and decreased IL-1α-induced COX-2 mRNA expression. Thus, in odontogenic keratocyst fibroblasts, IL-1αmay stimulate COX-2 expression both through the PKC-dependent activation of ERK1/2, p38, and JNK signaling pathways, and through the NF-κB cascade.

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