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 whether 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 lauric acid-induced Nod2 signaling, leading to the suppression of nuclear factor-κB activation and target gene interleukin-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 for the first time 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 remains to be determined whether these phytochemicals possess protective or therapeutic efficacy against Nod2-mediated inflammatory disorders.
Footnotes
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This work was supported by National Institutes of Health grants DK064007, DK41868, and CA75613; United States Department of Agriculture (USDA) grant 2001-35200-10721; American Institutes for Cancer Research grant 01A095Rev; and program funds from the Western Human Nutrition Research Center, USDA Agricultural Research Service.
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ABBREVIATIONS: TLR, Toll-like receptor; PRR, pattern recognition receptor; NOD, the nucleotide-binding oligomerization domain family; LRR, leucine-rich repeat domain; NACHT, domain present in NAIP (neuronal apoptosis inhibitory protein), CIITA (MHC class II transcription activator), HET-E (incompatibility locus protein from Podospora anserine), and TP1 (telomerase-associated protein); NF-κB, nuclear factor-κB; MDP, muramyl dipeptide MurNAc-l-Ala-d-isoGln; IKK, IκB kinase complex; IκB, inhibitor of NF-κB; EGCG, epigallocatechin gallate; HA, hemagglutinin; HEK, human embryonic kidney; IL, interleukin; Luc, luciferase; RICK, Rip-like interacting CLARP kinase; ELISA, enzyme-linked immunosorbent assay; RLA, relative luciferase activity.
- Received February 8, 2008.
- Accepted April 10, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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