|Zhao, Ling - UC DAVIS, NUTR. DEPT.|
|Kim, Kihoon - INJE UNIV. KIMHAE,S.KOREA|
|Lee, Dong Seok - INJE UNIV. KIMHAE,S.KOREA|
Submitted to: Molecular Pharmacology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: April 10, 2008
Publication Date: May 1, 2008
Repository URL: http://molpharm.aspetjournals.org/content/74/1/274.full.pdf+html
Citation: Huang, S., Zhao, L., Kim, K., Lee, D., Hwang, D.H. 2008. Inhibition of Nod2 signaling and target gene expression by curcumin. Molecular Pharmacology 74(1):274-281, 2008. Interpretive Summary: Chronic inflammation is one of the key etiological conditions for the development and progression of many chronic diseases. Nod2 is one of the receptor proteins that mediate the immune responses. It can be activated by the invasion of pathogens as well as by certain dietary compounds, such as saturated fatty acids. Mutations in the Nod2 protein have been linked to the inflammatory granulomatous disorders, such as Crohn’s disease and Blau syndrome. Many compounds from plants possess anti-inflammatory properties. However, it is not known if any of these compounds might modulate Nod2-mediated immune responses and thus might be of therapeutic value for the intervention of these inflammatory diseases. In this report, we demonstrate that plant compounds curcumin and parthenolide both suppress Nod2-mediated inflammatory responses induced by bacterial product or dietary saturated fatty acid luric acid. It remains to be determined if these plant compounds posses protective or therapeutic efficacy against Nod2-mediated inflammatory disorders.
Technical Abstract: Nod2 is an intracellular pattern recognition receptor that detects a conserved moiety of bacterial peptidoglycan and subsequently activates proinflammatory signaling pathways. Mutations in Nod2 have been implicated to be linked to inflammatory granulomatous disorders, such as Crohn’s disease and Blau syndrome. Many phytochemicals possess anti-inflammatory properties. However, it is not known if any of these phytochemicals might modulate Nod2-mediated immune responses and thus might be of therapeutic value for the intervention of these inflammatory diseases. In this report, we demonstrate that curcumin, a polyphenol found in the plant Curcuma longa, and parthenolide, a sesquiterpene lactone, suppress both ligand-induced and luric acid-induced Nod2 signaling leading to the suppression of NF-'B activation and target gene IL-8 expression. We provide molecular and biochemical evidence that the suppression is mediated through the inhibition of Nod2 oligomerization and subsequent inhibition of downstream signaling. These results demonstrate that curcumin and parthenolide can directly inhibit Nod2-mediated signaling pathways at the receptor level and suggest that Nod2-mediated inflammatory responses can be modulated by these phytochemicals. It needs to be determined whether these phytochemicals possess protective or therapeutic efficacy against Nod2-mediated inflammatory disorders.