Identification of the Synthetic Cannabinoid R(+)WIN55,212-2 as a Novel Regulator of IFN Regulatory Factor 3 Activation and IFN-β Expression

Downer, Eric J.; Clifford, Eileen; Gran, Bruno; Nel, Hendrik J.; Fallon, Padraic G.; Moynagh, Paul N.

doi:10.1074/jbc.m110.188599

Cited by 38 publications

(41 citation statements)

References 51 publications

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“…R(ϩ)WIN55,212-2 is a potent synthetic cannabinoid receptor agonist and while capable of binding to both CB 1 and CB 2 cannabinoid receptors, it exhibits greater selectivity for CB 2 (9). However, we have demonstrated cannabinoid receptor-independent mechanisms of action for R(ϩ)WIN55,212-2, including those underlying its regulation of IFN-␤ expression (8). Such findings and others clearly indicate that R(ϩ)-WIN55,212-2 can work independently of the classical cannabinoid receptor system.…”

mentioning

confidence: 70%

“…Given that such effects were shown to be mediated in a manner independent of cannabinoid receptors (8,37) and that this compound can exert some effects via PPAR␣ (13, 38), we used the specific PPAR␣ antagonist GW6471 to assess the potential role of PPAR␣ in mediating the effects of R(ϩ)WIN55,212-2 on TLR3-induced activation of NF-B and IRF3 and expression of TLR-responsive genes. GW6471 failed to regulate the ability of R(ϩ)WIN55,212-2 to inhibit TLR3-induced activation of NF-B in HEK293-TLR3 cells (Fig.…”

Section: R(ϩ)win55212-2 Enhances Tlr3-induced Ifn-␤ Expression Via Pmentioning

confidence: 99%

“…,212-2 negatively regulates the transactivation of NF-B and expression of proinflammatory cytokines (37) but can positively impact the TLR3-IRF3 signaling axis to enhance IFN-␤ expression in the presence of TLR3 stimulation (8). Given that such effects were shown to be mediated in a manner independent of cannabinoid receptors (8,37) and that this compound can exert some effects via PPAR␣ (13, 38), we used the specific PPAR␣ antagonist GW6471 to assess the potential role of PPAR␣ in mediating the effects of R(ϩ)WIN55,212-2 on TLR3-induced activation of NF-B and IRF3 and expression of TLR-responsive genes.…”

Section: R(ϩ)win55212-2 Enhances Tlr3-induced Ifn-␤ Expression Via Pmentioning

confidence: 99%

“…PRDI-III domains are recognized by IFN regulatory factors (IRFs) (3 and 7), PRDII by nuclear factor-B (NF-B) and PRDIV by activator protein-1 (AP-1) (ATF-2/c-Jun), and these transcription factors act in co-operation to form an enhanceosome that drives efficient production of IFN-␤ (7). Intriguingly, we have recently demonstrated that the aminoalkylindole, R(ϩ)WIN55,212-2, regulates IFN-␤ expression by augmenting activation of IRF3 and this is critical for manifesting its protective effects in experimental autoimmune encephalomyelitis (EAE), an animal model of MS (8). R(ϩ)WIN55,212-2 is a potent synthetic cannabinoid receptor agonist and while capable of binding to both CB 1 and CB 2 cannabinoid receptors, it exhibits greater selectivity for CB 2 (9).…”

mentioning

confidence: 99%

“…Despite the integral role of TLRs in pathogen recognition, dysregulation of TLR signaling cascades is associated with inflammation (24). We have previously demonstrated that R(ϩ)WIN55,212-2 differentially regulates TLR signaling (TLR3 and TLR4), and in particular, this aminoalkylindole derivative acts as a novel regulator of TLR3 signaling to IRF3 and subsequent expression of IFN-␤ (8). Such effects of R(ϩ)WIN55,212-2, in particular its capacity to induce endogenous IFN-␤, offers an attractive additional option to the current use of exogenously administered IFN-␤ in MS.…”

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confidence: 99%

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The Synthetic Cannabinoid R(+)WIN55,212-2 Augments Interferon-β Expression via Peroxisome Proliferator-activated Receptor-α

Downer

Clifford

Amu

et al. 2012

Journal of Biological Chemistry

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confidence: 70%

Section: R(ϩ)win55212-2 Enhances Tlr3-induced Ifn-␤ Expression Via Pmentioning

confidence: 99%

Section: R(ϩ)win55212-2 Enhances Tlr3-induced Ifn-␤ Expression Via Pmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The Synthetic Cannabinoid R(+)WIN55,212-2 Augments Interferon-β Expression via Peroxisome Proliferator-activated Receptor-α

Downer

Clifford

Amu

et al. 2012

Journal of Biological Chemistry

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Interferon regulatory factor 3 inhibits astrocyte inflammatory gene expression through suppression of the proinflammatory miR‐155 and miR‐155*

Tarassishin

Loudig

Bauman

et al. 2011

Glia

116

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Astrocytes, together with microglia and macrophages, participate in innate inflammatory responses in the CNS. While inflammatory mediators such as interferons generated by astrocytes may be critical in the defense of the CNS, sustained unopposed cytokine signaling could result in harmful consequences. Interferon regulatory factor 3 (IRF3) is a transcription factor required for IFNβ production and antiviral immunity. Most cells express low levels of IRF3 protein and the transcriptional mechanism that upregulates IRF3 expression is not known. In the current study, we explored the consequence of adenovirus-mediated IRF3 gene transfer (Ad-IRF3) in primary human astrocytes. We show that IRF3 transgene expression suppresses proinflammatory cytokine gene expression upon challenge with IL-1/IFNγ and alters astrocyte activation phenotype from a proinflammatory to an anti-inflammatory one, akin to an M1 to M2 switch in macrophages. This was accompanied by the rescue of neurons from cytokine-induced death in glial-neuronal cocultures. Furthermore, Ad-IRF3 suppressed the expression of microRNA-155 and its star-form partner miR-155*, immunoregulatory miRNAs highly expressed in multiple sclerosis lesions. Astrocyte miR-155/miR155* were induced by cytokines and TLR ligands with a distinct hierarchy, and were involved in proinflammatory cytokine gene induction by targeting suppressor of cytokine signaling 1 (SOCS1), a negative regulator of cytokine signaling and potentially other factors. Our results demonstrate a novel pro-inflammatory role for miR-155/miR-155* in human astrocytes, and suggest that IRF3 can suppress neuroinflammation through regulating immunomodulatory miRNA expression.

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LPS and IL‐1 differentially activate mouse and human astrocytes: Role of CD14

Tarassishin

Suh

Lee

2014

Glia

174

126

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Treatment of cultures with toll-like receptor (TLR) ligands or cytokines has become a popular approach to investigate astrocyte neuroinflammatory responses and to simulate the neural environment in various CNS disorders. However, despite much effort, the mechanism of astrocyte activation such as their responses to the TLR ligands and IL-1 remain highly debated. We compared highly pure primary mouse and human astrocyte cultures in their ability to produce proinflammatory mediators (termed “A1”) and immunoregulatory mediators (termed “A2”) in response to LPS, poly IC and IL-1 stimulation. In human astrocytes, IL-1 induced both A1 and A2 responses, poly IC induced mostly A2, and LPS induced neither. In mouse astrocytes, LPS induced mostly an A1 predominant response, poly IC induced both A1 and A2, and IL-1 neither. In addition, mouse astrocytes produce abundant IL-1 protein while human astrocytes did not, despite robust IL-1 mRNA expression. Of the TLR4 receptor complex proteins, human astrocytes expressed TLR4 and MD2 but not CD14, while mouse astrocytes expressed all three. Mouse astrocyte CD14 (cell-associated and soluble) was potently upregulated by LPS. Silencing TLR4 or CD14 by siRNA suppressed LPS responses in mouse astrocytes. In vivo, astrocytes in LPS-injected mouse brains also expressed CD14. Our results show striking differences between human and mouse astrocytes in the use of TLR/IL-1R and subsequent downstream signaling and immune activation. IL-1 translational block in human astrocytes may be a built-in mechanism to prevent autocrine and paracrine cell activation and neuroinflammation. These results have important implications for translational research of human CNS diseases.

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Identification of the Synthetic Cannabinoid R(+)WIN55,212-2 as a Novel Regulator of IFN Regulatory Factor 3 Activation and IFN-β Expression

Cited by 38 publications

References 51 publications

The Synthetic Cannabinoid R(+)WIN55,212-2 Augments Interferon-β Expression via Peroxisome Proliferator-activated Receptor-α

The Synthetic Cannabinoid R(+)WIN55,212-2 Augments Interferon-β Expression via Peroxisome Proliferator-activated Receptor-α

Interferon regulatory factor 3 inhibits astrocyte inflammatory gene expression through suppression of the proinflammatory miR‐155 and miR‐155*

LPS and IL‐1 differentially activate mouse and human astrocytes: Role of CD14

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