Back to Search
Start Over
TRPM2 contributes to LPS/IFNγ-induced production of nitric oxide via the p38/JNK pathway in microglia.
- Source :
-
Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2014 Feb 07; Vol. 444 (2), pp. 212-7. Date of Electronic Publication: 2014 Jan 22. - Publication Year :
- 2014
-
Abstract
- Microglia are immune cells that maintain brain homeostasis at a resting state by surveying the environment and engulfing debris. However, in some pathological conditions, microglia can produce neurotoxic factors such as pro-inflammatory cytokines and nitric oxide (NO) that lead to neuronal degeneration. Inflammation-induced calcium (Ca(2+)) signaling is thought to underlie this abnormal activation of microglia, but the mechanisms are still obscure. We previously showed that combined application of lipopolysaccharide and interferon γ (LPS/IFNγ) induced-production of NO in microglia from wild-type (WT) mice is significantly reduced in microglia from transient receptor potential melastatin 2 (TRPM2)-knockout (KO) mice. Here, we found that LPS/IFNγ produced a late-onset Ca(2+) signaling in WT microglia, which was abolished by application of the NADPH oxidase inhibitor diphenylene iodonium (DPI) and ML-171. In addition, pharmacological blockade or gene deletion of TRPM2 channel in microglia did not show this Ca(2+) signaling. Furthermore, pharmacological manipulation and Western blotting revealed that Ca(2+) mobilization, the proline-rich tyrosine kinase 2 (Pyk2), p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun NH2-terminal kinase (JNK) contributed to TRPM2-mediated LPS/IFNγ-induced activation, while the extracellular signal-regulated protein kinase (ERK) did not. These results suggest that LPS/IFNγ activates TRPM2-mediated Ca(2+) signaling, which in turn increases downstream p38 MAPK and JNK signaling and results in increased NO production in microglia.<br /> (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Blotting, Western
Calcium metabolism
Cells, Cultured
Chelating Agents pharmacology
Egtazic Acid analogs & derivatives
Egtazic Acid pharmacology
Enzyme Inhibitors pharmacology
Focal Adhesion Kinase 2 antagonists & inhibitors
Focal Adhesion Kinase 2 metabolism
JNK Mitogen-Activated Protein Kinases antagonists & inhibitors
JNK Mitogen-Activated Protein Kinases metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Miconazole pharmacology
Microglia metabolism
NADPH Oxidases antagonists & inhibitors
NADPH Oxidases metabolism
Nitriles
TRPM Cation Channels antagonists & inhibitors
TRPM Cation Channels metabolism
Tyrphostins pharmacology
p38 Mitogen-Activated Protein Kinases antagonists & inhibitors
p38 Mitogen-Activated Protein Kinases metabolism
Interferon-gamma pharmacology
Lipopolysaccharides pharmacology
MAP Kinase Signaling System drug effects
Microglia drug effects
Nitric Oxide biosynthesis
TRPM Cation Channels genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2104
- Volume :
- 444
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Biochemical and biophysical research communications
- Publication Type :
- Academic Journal
- Accession number :
- 24462864
- Full Text :
- https://doi.org/10.1016/j.bbrc.2014.01.022