Suppression of the inflammatory response by triterpenes isolated from the mushroom Ganoderma lucidum.
Ganoderma lucidum is a popular medicinal mushroom, which has been used in the Traditional Chinese medicine for the prevention or treatment of a variety of diseases. In the present study we evaluated the anti-inflammatory effects of the triterpene extract from G. lucidum (GLT) in LPS-stimulated macrophages. Here we show that GLT markedly suppressed the secretion of inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), and inflammatory mediator nitric oxide (NO) and prostaglandin E(2) (PGE(2)) from lipopolysaccharide (LPS)-stimulated murine RAW264.7 cells. GLT also down-regulated LPS-dependent expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) in RAW264.7 cells. The anti-inflammatory effects of GLT were mediated by the inhibition of transcription factor NF-kappaB as demonstrated by decreased NF-kappaB-DNA binding activity, and the suppression of p65 phosphorylation in LPS-stimulated macrophages treated with GLT. Moreover, GLT inhibited LPS-dependent AP-1-DNA binding activity and down-regulated expression of AP-1 subunit c-Jun. In addition, GLT suppressed the activity of MAP kinases as observed by the down-regulation of LPS-induced phosphorylation of ERK1/2 and JNK but not p38. In vivo experiments clearly demonstrated that GLT also inhibited the production of TNF-alpha and IL-6 in LPS-induced endotoxemic mice. Apart from its anti-inflammatory activity, GLT suppressed cell proliferation of RAW264.7 cells through cell cycle arrest at G0/G1-G2M, which was mediated by the down-regulation of expression of cell cycle regulatory proteins cyclin D1, CDK4 and cyclin B1, respectively. In conclusion, the anti-inflammatory and anti-proliferative effects of GLT on macrophages are mediated through the inhibition of NF-kappaB and AP-1 signaling pathways.
Dudhgaonkar
Shailesh
S
Cancer Research Laboratory, Methodist Research Institute, 1800 N Capitol Ave, E504, Indianapolis, IN 46202, USA.
Thyagarajan
Anita
A
Sliva
Daniel
D
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D020940:Reishi / Q000737:chemistry; D014315:Triterpenes / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D004365:Drugs, Chinese Herbal; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D014315:Triterpenes