Potent anti-inflammatory activity of ursolic acid, a triterpenoid antioxidant, is mediated through suppression of NF-κB, AP-1 and NF-AT.

Abstract

BACKGROUND:

Ursolic acid (UA), a pentacyclic triterpenoid carboxylic acid, is the major component of many plants including apples, basil, cranberries, peppermint, rosemary, oregano and prunes and has been reported to possess antioxidant and anti-tumor properties. These properties of UA have been attributed to its ability to suppress NF-κB (nuclear factor kappa B) activation. Since NF-κB, in co-ordination with NF-AT (nuclear factor of activated T cells) and AP-1(activator protein-1), is known to regulate inflammatory genes, we hypothesized that UA might exhibit potent anti-inflammatory effects.

METHODOLOGY/PRINCIPAL FINDINGS:

The anti-inflammatory effects of UA were assessed in activated T cells, B cells and macrophages. Effects of UA on ERK, JNK, NF-κB, AP-1 and NF-AT were studied to elucidate its mechanism of action. In vivo efficacy of UA was studied using mouse model of graft-versus-host disease. UA inhibited activation, proliferation and cytokine secretion in T cells, B cells and macrophages. UA inhibited mitogen-induced up-regulation of activation markers and co-stimulatory molecules in T and B cells. It inhibited mitogen-induced phosphorylation of ERK and JNK and suppressed the activation of immunoregulatory transcription factors NF-κB, NF-AT and AP-1 in lymphocytes. Treatment of cells with UA prior to allogenic transplantation significantly delayed induction of acute graft-versus-host disease in mice and also significantly reduced the serum levels of pro-inflammatory cytokines IL-6 and IFN-γ. UA treatment inhibited T cell activation even when added post-mitogenic stimulation demonstrating its therapeutic utility as an anti-inflammatory agent.

CONCLUSIONS/SIGNIFICANCE:

The present study describes the detailed mechanism of anti-inflammatory activity of UA. Further, UA may find application in the treatment of inflammatory disorders.

• Authors: Rahul Checker, Santosh K Sandur, Deepak Sharma, Raghavendra S Patwardhan, S Jayakumar, Vineet Kohli, Gautam Sethi, Bharat B Aggarwal, Krishna B Sainis
• Journal: PloS one (PLoS One) Vol. 7 Issue 2 Pg. e31318 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22363615 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Antibodies, Monoclonal
• Antioxidants
• CD28 Antigens
• CD3 Complex
• Cytokines
• Mitogens
• NF-kappa B
• NFATC Transcription Factors
• Reactive Oxygen Species
• Transcription Factor AP-1
• Triterpenes
• Concanavalin A
• Mitogen-Activated Protein Kinases

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Antibodies, Monoclonal (pharmacology)
• Antioxidants (pharmacology)
• B-Lymphocytes (cytology, drug effects, enzymology, metabolism)
• CD28 Antigens (immunology)
• CD3 Complex (immunology)
• CD4-Positive T-Lymphocytes (cytology, drug effects, enzymology, metabolism)
• CD8-Positive T-Lymphocytes (cytology, drug effects, enzymology, metabolism)
• Cell Proliferation (drug effects)
• Concanavalin A (pharmacology)
• Cytokines (metabolism)
• Graft vs Host Disease (immunology, pathology)
• Lymphocyte Activation (drug effects, genetics)
• Macrophages (cytology, drug effects, metabolism)
• Mice
• Mitogen-Activated Protein Kinases (metabolism)
• Mitogens (pharmacology)
• NF-kappa B (metabolism)
• NFATC Transcription Factors (metabolism)
• Oxidation-Reduction (drug effects)
• Reactive Oxygen Species (metabolism)
• Transcription Factor AP-1 (metabolism)
• Triterpenes (pharmacology)
• Up-Regulation (drug effects)
• Ursolic Acid