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Bcl-2 is a negative regulator of interleukin-1beta secretion in murine macrophages in pharmacological-induced apoptosis.

AbstractBACKGROUND 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-1beta 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-1beta 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-1beta. Finally, the transfection of RAW 264.7 macrophages with a Bcl-2 expression plasmid produced the inhibition of apoptosis and caspase-1 activation/interleukin-1beta 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-1beta release is directly regulated by Bcl-2 status; this contributes to the evidence that apoptotic processes do not induce inflammation.
AuthorsJ M Escandell, M C Recio, R M Giner, S Máñez, J L Ríos
JournalBritish journal of pharmacology (Br J Pharmacol) Vol. 160 Issue 7 Pg. 1844-56 (Aug 2010) ISSN: 1476-5381 [Electronic] England
PMID20649584 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Anti-Inflammatory Agents, Non-Steroidal
  • Interleukin-1beta
  • Lipopolysaccharides
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Small Interfering
  • Triterpenes
  • cucurbitacin R
  • Caspase 3
  • Caspase 1
Topics
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
  • Apoptosis (drug effects, immunology)
  • Blotting, Western
  • Caspase 1 (genetics, metabolism)
  • Caspase 3 (metabolism)
  • Cell Cycle (drug effects)
  • Cell Line
  • Flow Cytometry
  • Interleukin-1beta (metabolism)
  • Lipopolysaccharides (pharmacology)
  • Macrophages (drug effects, immunology, metabolism, pathology)
  • Membrane Potential, Mitochondrial (drug effects)
  • Mice
  • Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, biosynthesis, genetics)
  • RNA, Small Interfering (genetics)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transfection
  • Triterpenes (pharmacokinetics)

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