|Kwon, Myung Ja|
Submitted to: Journal of Biological Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/7/2007
Publication Date: 4/20/2007
Citation: Zhao, L., Kwon, M., Lee, J.Y., Fukase, K., Inohara, N., Hwang, D.H. 2007. Differential Modulation of Nods Signaling Pathways by Fatty Acids in Human Colonic Epithelial HCT116 cells. Journal of Biological Chemistry. Vol.282, No.16,pp.11618-11628. Interpretive Summary: We demonstrated the differential modulation of Nods siganling by fatty acids in human colonic epithelial cells and our results provided the new insight into the roles of fatty acids in inflammatory responses in gut and suggest the intracellular innate immunity receptor Nods proteins might be involved in inducing sterile inflammation,one of the key etiological conditions in the development of many chronic inflammatory diseases.
Technical Abstract: Nucleotide-binding oligomerization domain containing proteins (Nods) are intracellular pattern recognition receptors (PRRs) recognizing conserved moieties of bacterial peptidoglycan through their leucine-rich repeats (LRR) domain. The agonists for Nods activate proinflammtory signaling pathways including NF-'B pathways. The results from our previous studies showed that the activation of TLR4 and TLR2, LRR containing PRRs, were differentially modulated by saturated and n-3 polyunsaturated fatty acids in macrophages and dendritic cells. Here, we show the differential modulation of NF-'B activation and IL-8 expression in colonic epithelial cells HCT116 by saturated and unsaturated fatty acids mediated through Nods proteins. Lauric acid (C12:0) dose dependently activated NF-'B and IL-8 in HCT116 cells, which express both Nod1 and Nod2, but not detectable amount of TLR2 and TLR4. This activation was inhibited by dominant negative forms of Nod1 or Nod2, but not by dominant negative forms of TLR2, TLR4 and TLR5. The activation was also attenuated by small RNA interfence (siRNA) targeting Nod1 or Nod2. In addition, capric acid (C10:0) and myristic acid (C14:0) also activated the target gene IL-8. In contrast, polyunsaturated fatty acids, especially (n-3) PUFA nhibited the activation induced by lauric acid or known Nods ligand, i.e., iE-DAP and MDP for Nod1 and Nod2, respectively in HCT116. Furthermore, lauric acid induced, but docosahexaenoic acid (DHA)inhibited lauric acid- or Nod2 ligand MDP-induced, Nod2 oligomerization in HEK293T cells transfected with Nod2. Together, these results provide new insights into the role of dietary fatty acids in modulating inflammation in colon epithelial cells and suggest that Nods may be involved in inducing sterile inflammation, one of the key etiological conditions in the development of many chronic inflammatory diseases.