Celastrol inhibits production of nitric oxide and proinflammatory cytokines through MAPK signal transduction and NF-κB in LPS-stimulated BV-2 microglial cells

Abstract

Excessive production of nitric oxide (NO) and proinflammatory cytokines from activated microglia play an important role in human neurodegenerative disorders. Here, we investigated whether celastrol, which has been used as a potent anti-inflammatory and anti-oxidative agent in Chinese medicine, attenuates excessive production of NO and proinflammatory cytokines such as TNF-α and IL-1β in LPS-stimulated BV-2 cells, a mouse microglial cell line. We report here that the LPS-elicited excessive production of NO, TNF-α , and IL-1β in BV-2 cells was largely inhibited in the presence of celastrol, and the attenuation of inducible iNOS and these cytokines resulted from the reduced expression of mRNAs of iNOS and these cytokines, respectively. The molecular mechanisms that underlie celastrol-mediated attenuation were the inhibition of LPS-induced phosphorylation of MAPK/ERK1/2 and the DNA binding activity of NF-κ B in BV-2 cells. The results indicate that celastrol effectively attenuated NO and proinflammatory cytokine production via the inhibition of ERK1/2 phosphorylation and NF-κ B activation in LPS-activated microglia. Thus, celastrol may be an effective therapeutic candidate for use in the treatment of neurodegenerative human brain disorders.

ATF2 contributes to cisplatin resistance in non‐small cell lung cancer and celastrol induces cisplatin resensitization through inhibition of JNK/ATF2 pathway

“…Celastrol affects several biological processes through the inhibition of ATF2, nuclear factor-KB, inducible NOS, VEGF receptors, HSP90, potassium/calcium channel and eventually increases the reactive oxygen species (ROS) in cancer cells, thus in turn activating apoptosis pathways. 16,22,[25][26][27][28][29] In the present study, we investigated whether ATF2 could contribute to primary and/or acquired drug resistance in NSCLC. We demonstrated that high expression levels of ATF2, at transcript and protein levels, are detected in NSCLC and ATF2 protein activation correlates with worse outcome in advanced NSCLC patients cisplatin-treated.…”

Celastrol regulates multiple nuclear transcription factors belonging to HSP90's clients in a dose- and cell type-dependent way

“…In recent years, celastrol has attracted attention due to its potential for use in anti-inflammation (Jung et al 2007;Kim et al 2009a, b;Pinna et al 2004), anti-tumor (Dai et al 2009;Ge et al 2010;He et al 2009a), and neuron degenerative disease amelioration applications (Allison et al 2001;Faust et al 2009;Kiaei et al 2005). Celastrol can inhibit NF-κB activation (He et al 2009a;Jung et al 2007; Lee et al 2006), arrest cell cycle (Ge et al 2010), and induce heat shock and anti-oxidant response (Faust et al 2009, Westerheide et al 2004. The most recent reports attribute these effects to an attack on the heat shock protein (HSP90) complex by celastrol (Zhang et al 2008).…”

Gua Lou Gui Zhi decoction suppresses LPS-induced activation of the TLR4/NF-κB pathway in BV-2 murine microglial cells

“…On the contrary, after cells receive pathological stimuli, IκB protein is phosphorylated, a process leading to its ubiquitination and degradation. Consequently, released NF-κB translocates to the nucleus where it induces the expression of pro-inflammatory mediators (26). Using western blotting and immunofluorescence staining analyses, we found that GLGZD treatment significantly decreased the protein expression of TLR4 and MyD88, inhibited the phosphorylation of IκB and blocked the nuclear translocation of NF-κB in BV-2 cells, suggesting that GLGZD suppresses the activation of the TLR4/NF-κB signaling pathway.…”