Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 160, Issue 7, Pages 1844-1856Publisher
WILEY
DOI: 10.1111/j.1476-5381.2010.00856.x
Keywords
apoptosis; cucurbitacin R; interleukin-1 beta; Bcl-2; caspase-1; RAW 264; 7 macrophages
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Funding
- Spanish Government [SAF2006-06726]
- EU
- Generalitat Valenciana [CTBPRB/2003/315]
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BACKGROUND AND PURPOSE Cucurbitacin R, a natural anti-inflammatory product, has been shown to exhibit activity against both adjuvant-induced arthritis and delayed-type hypersensitivity reactions induced by various agents. Previous studies have demonstrated that the effects of cucurbitacin R stem from its inhibition of both cytokine production and lymphocyte proliferation. EXPERIMENTAL APPROACHES Effects of cucurbitacin R were investigated on lipopolysaccharide-stimulated RAW 264.7 cells. Cell cycle evolution was analysed by flow cytometry, detection of apoptosis by DNA ladder, Bcl-2, p21, p53, Bax, cleaved caspase-1 (p10), caspase-9, and caspase-3, cleaved caspase (p17) and interleukin-1 beta detection was followed by Western blot analysis and mRNA expression with quantitative real time reverse transcription-polymerase chain reaction (qRT-PCR). KEY RESULTS Cucurbitacin R was found to induce apoptosis in lipopolysaccharide-stimulated RAW 264.7 macrophages through the inhibition of Bcl-2 expression, which regulates pro-inflammatory caspase-1 activation and interleukin-1 beta release. Also, cucurbitacin R arrested the cell cycle in the G(2)/M phase and increased the subG(0) population in lipopolysaccharide-stimulated RAW 264.7 macrophages. Moreover, it increased the expression of proteins p53 and p21, down-regulated the expression of Bcl-2, activated the activity of caspase-1 and augmented the production of interleukin-1 beta. Finally, the transfection of RAW 264.7 macrophages with a Bcl-2 expression plasmid produced the inhibition of apoptosis and caspase-1 activation/interleukin-1 beta release induced by cucurbitacin R in RAW 264.7 cells. CONCLUSIONS AND IMPLICATIONS Taken together, these results point to a new apoptotic process in which interleukin-1 beta release is directly regulated by Bcl-2 status; this contributes to the evidence that apoptotic processes do not induce inflammation.
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