Inhibition of nitric oxide production by the carbazole compound LCY-2-CHO via blockade of activator protein-1 and CCAAT/enhancer-binding protein activation in microglia

Chang, Ling‐Chu; Tsao, Lo‐Ti; Chang, Cheng-Chen; Chen, Chun‐Jung; Huang, Le-Tian; Kuo, Sheng‐Chu; Lin, Ruey-Hseng; Wang, Jih-Pyang

doi:10.1016/j.bcp.2008.06.002

Cited by 42 publications

(27 citation statements)

References 43 publications

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“…No cytotoxic activity of 3-methylcarbazoles was observed under the same conditions (Figure 4), indicating that the immunopharmacological effect of 3-methylcarbazoles was not related to cy- totoxicity. As found with other carbazoles such as 9-(2-chlorobenyl)-9H-carbazole-3-carbaldehyde suppressed the NO production in LPS/interferon-γ-stimulated murine microglial cells [37] and LPS-stimulated murine RAW264.7 cells [38]. These results imply that the inhibitory activity of 3-methylcarbazoles is derived from its ability to block TLR-mediated inflammatory responses.…”

Section: T Taechowisan Et Alsupporting

confidence: 52%

Anti-Inflammatory Effect of 3-Methylcarbazoles on RAW 264.7 Cells Stimulated with LPS, Polyinosinic-Polycytidylic Acid and Pam3CSK

Taechowisan¹,

Chanaphat²,

Ruensamran³

et al. 2012

AiM

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In the present study, 3-methylcarbazole and 1-methoxy-3-methylcarbazole were isolated from the culture of Streptomyces sp. LJK109, endophyte of Alpinia galanga Swartz. 3-methylcarbazole, a carbazole derivative, has been found to be highly potent as anti-inflammatory agent. The immunomodulatory activity of these agents in toll like receptor (TLR)-activated RAW 264.7 macrophages induced by lipopolysaccharide (LPS), Poly(I:C), and pam3CSK was investigated by assessing nitric oxide (NO) and pro-inflammatory cytokines. The 3-methylcarbazoles dose-dependently suppressed the release of NO, PGE 2 , TNF-α, IL-1β, IL-6 and IL-10 in LPS-and pam3CSK-activated macrophages but not in Poly(I:C)-activated macrophages. Our results suggest that 3-methylcarbazoles can be further developed as a promising anti-inflammatory remedy.

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Section: T Taechowisan Et Alsupporting

confidence: 52%

Anti-Inflammatory Effect of 3-Methylcarbazoles on RAW 264.7 Cells Stimulated with LPS, Polyinosinic-Polycytidylic Acid and Pam3CSK

Taechowisan¹,

Chanaphat²,

Ruensamran³

et al. 2012

AiM

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“…161 Like NF-B, the activation of AP-1 in microglia drives a proinflammatory response and the release of several cytotoxic agents. [162][163][164] …”

Section: Nf-b and Ap-1mentioning

confidence: 99%

Microglial Activation in Stroke: Therapeutic Targets

2010

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Summary:Microglial activation is an early response to brain ischemia and many other stressors. Microglia continuously monitor and respond to changes in brain homeostasis and to specific signaling molecules expressed or released by neighboring cells. These signaling molecules, including ATP, glutamate, cytokines, prostaglandins, zinc, reactive oxygen species, and HSP60, may induce microglial proliferation and migration to the sites of injury. They also induce a nonspecific innate immune response that may exacerbate acute ischemic injury. This innate immune response includes release of reactive oxygen species, cytokines, and proteases. Microglial activation requires hours to days to fully develop, and thus presents a target for therapeutic intervention with a much longer window of opportunity than acute neuroprotection. Effective agents are now available for blocking both microglial receptor activation and the microglia effector responses that drive the inflammatory response after stroke. Effective agents are also available for targeting the signal transduction mechanisms linking these events. However, the innate immune response can have beneficial as well deleterious effects on outcome after stoke, and a challenge will be to find ways to selectively suppress the deleterious effects of microglial activation after stroke without compromising neurovascular repair and remodeling.

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“…C/EBPβ activity is mainly regulated at the level of transcription (Bradley et al, 2003), therefore increased protein/mRNA levels of C/EBPβ are a good indicator of increased C/EBPβ activity as transcription factor. C/EBPβ expression in activated microglial cells has been reported in cultured microglia treated with TLR agonists (Chang et al, 2008;EjarqueOrtiz et al, 2007;Samuelsson et al, 2008), proinflammatory cytokines (Jana et al, 2001;Jana et al, 2002;Jana et al, 2003) or activated T lymphocytes . Increased C/EBPβ levels have also been reported in vivo in situations in which neuroinflammation occurs such as systemic LPS injection (Alam et al, 1992;EjarqueOrtiz et al, 2007;Saito et al, 1999;Damm et al, 2011), cerebral ischemia (Kapadia et al, 2006), excitotoxic insult (Cortes-Canteli et al, 2008) or aging (Akar and Feinstein, 2009 or IL-6 since these genes contain functional C/EBP sites in their promoters Kolyada and Madias, 2001;Ray and Ray, 1995;Wedel et al, 1996;Yang et al, 2000).…”

Section: C/ebpβ Is Expressed By Microglial Cells In Alsmentioning

confidence: 99%

C/EBPβ expression in activated microglia in amyotrophic lateral sclerosis

Valente

Mancera

Tusell

et al. 2012

Neurobiology of Aging

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Abstract.Neuroinflammation is thought to play a pathogenic role in many neurodegenerative disorders including amyotrophic lateral sclerosis (ALS). In this study we demonstrate that the expression of NO synthase-2 (NOS2) and cyclooxygenase-2 (COX-2) induced by lipopolysaccharide (LPS) + interferon-γ is higher in microglial-enriched cultures from G93A-SOD1 mice, an ALS animal model, than from wild-type mice. The levels of CCAAT/enhancer binding protein β (C/EBPβ), a transcription factor that regulates proinflammatory gene expression, are also upregulated in activated G93A-SOD1 microglial cells. In vivo, systemic LPS also induces an exacerbated neuroinflammatory response in G93A-SOD1 mice vs wild-type mice, with increased expression of GFAP, CD11b, NOS2, COX-2, proinflammatory cytokines and C/EBPβ. Finally, we report that C/EBPβ is expressed by microglia in the spinal cord of ALS patients. This is the first demonstration to our knowledge of microglial C/EBPβ expression in human disease.Altogether these findings indicate that G93A-SOD1 expression results in an exacerbated pattern of neuroinflammation and suggest that C/EBPβ is a candidate to regulate the expression of potentially neurotoxic genes in microglial cells in ALS.

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Inhibition of nitric oxide production by the carbazole compound LCY-2-CHO via blockade of activator protein-1 and CCAAT/enhancer-binding protein activation in microglia

Cited by 42 publications

References 43 publications

Anti-Inflammatory Effect of 3-Methylcarbazoles on RAW 264.7 Cells Stimulated with LPS, Polyinosinic-Polycytidylic Acid and Pam3CSK

Anti-Inflammatory Effect of 3-Methylcarbazoles on RAW 264.7 Cells Stimulated with LPS, Polyinosinic-Polycytidylic Acid and Pam3CSK

Microglial Activation in Stroke: Therapeutic Targets

C/EBPβ expression in activated microglia in amyotrophic lateral sclerosis

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