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The endocannabinoid anandamide downregulates IL-23 and IL-12 subunits in a viral model of multiple sclerosis: evidence for a cross-talk between IL-12p70/IL-23 axis and IL-10 in microglial cells.
- Source :
-
Brain, behavior, and immunity [Brain Behav Immun] 2011 May; Vol. 25 (4), pp. 736-49. Date of Electronic Publication: 2011 Feb 16. - Publication Year :
- 2011
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Abstract
- Theiler's virus (TMEV) infection of the central nervous system (CNS) induces an immune-mediated demyelinating disease in susceptible mouse strains and serves as a relevant infection model for human multiple sclerosis (MS). The endocannabinoid system represents a novel therapeutic target for autoimmune and chronic inflammatory diseases due to its anti-inflammatory properties by regulating cytokine network. IL-12p70 and IL-23 are functionally related heterodimeric cytokines that play a crucial role in the pathogenesis of MS. In the present study we showed that the endocannabinoid anandamide (AEA) downregulated the gene expression of IL-12p70 and IL-23 forming subunits mRNAs in the spinal cord of TMEV-infected mice and ameliorated motor disturbances. This was accompanied by significant decreases on the serological levels of IL-12p70/IL-23 and more interestingly, of IL-17A. In contrast, serum levels of IL-10 resulted elevated. In addition, we studied the signalling pathways involved in the regulation of IL-12p70/IL-23 and IL-10 expression in TMEV-infected microglia and addressed the possible interactions of AEA with these pathways. AEA acted through the ERK1/2 and JNK pathways to downregulate IL-12p70 and IL-23 while upregulating IL-10. These effects were partially mediated by CB2 receptor activation. We also described an autocrine circuit of cross-talk between IL-12p70/IL-23 and IL-10, since endogenously produced IL-10 negatively regulates IL-12p70 and IL-23 cytokines in TMEV-infected microglia. This suggests that by altering the cytokine network, AEA could indirectly modify the type of immune responses within the CNS. Accordingly, pharmacological modulation of endocannabinoids might be a useful tool for treating neuroinflammatory diseases.<br /> (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Subjects :
- Adaptive Immunity drug effects
Analysis of Variance
Animals
Cardiovirus Infections drug therapy
Cardiovirus Infections virology
Disease Models, Animal
Down-Regulation
Female
Interleukin-10 genetics
Interleukin-10 immunology
Interleukin-10 metabolism
Interleukin-12 genetics
Interleukin-12 immunology
Interleukin-12 metabolism
Interleukin-23 drug effects
Interleukin-23 genetics
Interleukin-23 metabolism
Interleukins genetics
Interleukins metabolism
Mice
Microglia metabolism
Microglia virology
Multiple Sclerosis immunology
Multiple Sclerosis metabolism
Nervous System Autoimmune Disease, Experimental metabolism
Nervous System Autoimmune Disease, Experimental virology
Neuroimmunomodulation drug effects
Protein Subunits
RNA, Messenger analysis
Receptor Cross-Talk
Signal Transduction
Statistics, Nonparametric
Theilovirus immunology
Arachidonic Acids pharmacology
Cannabinoid Receptor Modulators pharmacology
Cardiovirus Infections immunology
Endocannabinoids
Interleukins immunology
Microglia immunology
Nervous System Autoimmune Disease, Experimental immunology
Polyunsaturated Alkamides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2139
- Volume :
- 25
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Brain, behavior, and immunity
- Publication Type :
- Academic Journal
- Accession number :
- 21310228
- Full Text :
- https://doi.org/10.1016/j.bbi.2011.01.020