Background & Aims
NOD-like receptors are recently described cytosolic pattern recognition receptors.
NOD1 and NOD2 are members of this family that recognize bacterial cell wall components,
diaminopimelic acid and muramyl dipeptide, respectively. Both NOD1 and NOD2 have been
associated with many inflammatory diseases, although their role in liver inflammation
and infection has not been well studied.
Methods
We investigated the role of NOD receptors in mouse liver by assessing expression and
activation of NOD1 and NOD2 in liver and primary isolated hepatocytes from C57BL/6
mice.
Results
Both NOD1 and NOD2 mRNA and protein were highly expressed in hepatocytes and liver.
RIP2, the main signaling partner for NODs, was also expressed. Stimulation of hepatocytes
with NOD1 ligand (C12-iEDAP) induced NFκB activation, activation of MAP kinases and
expression of chemokines CCL5 (RANTES) and CXCL1 (KC). C12-iEDAP also synergized with
interferon (IFN)γ to increase iNOS expression and production of nitric oxide. Despite
activating NFκB, NOD1 ligand did not upregulate hepatocyte production of the acute
phase proteins lipopolysaccharide binding protein, serum amyloid A, or soluble CD14
in cell culture supernatants, or upregulate mRNA expression of lipopolysaccharide
binding protein, serum amyloid A, C-reactive protein, or serum amyloid P. NOD2 ligand
(MDP) did not activate hepatocytes when given alone, but did synergize with Toll-like
receptor ligands, lipopolysaccharide (LPS), and polyI:C to activate NFκB and MAPK.
Conclusions
All together these data suggest an important role for hepatocyte NOD1 in attracting
leukocytes to the liver during infection and for hepatic NLRs to augment innate immune
responses to pathogens.
Abbreviations:
NOD (nucleotide oligomerization domain), NLR (NOD-like receptor), TLR (Toll-like receptor), NALP (NACHT leucine-rich repeat and pyrin domain containing protein), CARD (caspase activation and recruitment domain), RIP2 (receptor-interacting protein kinase), IL (interleukin), DAP (diaminopimelic acid), PGN (peptidoglycan), MDP (muramyl dipeptide), NO (nitric oxide), LPS (lipopolysaccharide), RANTES (regulated on activation normal T cell expressed and secreted), MIG (monokine induced by IFN-gamma), KC (keratinocyte-derived chemokine), MCP1 (monocyte chemotactic protein 1), SAA (serum amyloid A), SAP (serum amyloid P), LBP (lipopolysaccharide binding protein), CRP (C-reactive protein)Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of HepatologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Nod-like proteins in immunity, inflammation and disease.Nat Immunol. 2006; 7: 1250-1257
- NACHT-LRR proteins (NLRs) in bacterial infection and immunity.Trends Microbiol. 2005; 13: 381-388
- NALPs: a novel protein family involved in inflammation.Nat Rev Mol Cell Biol. 2003; 4: 95-104
- A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-κB activation.EMBO J. 2008; 27: 373-383
- PH-dependent internalization of muramyl peptides from early endosomes enables Nod1 and Nod2 signaling.J Biol Chem. 2009; 284: 23818-23829
- The hepatocyte as a microbial product-responsive cell.J Endotoxin Res. 2001; 7: 365-373
- Beta2-integrin-induced p38 MAPK activation is a key mediator in the CD14/TLR4/MD2-dependent uptake of lipopolysaccharide by hepatocytes.J Biol Chem. 2008; 283: 29433-29446
- Endotoxin uptake in mouse liver is blocked by endotoxin pretreatment through a suppressor of cytokine signaling-1-dependent mechanism.Hepatology. 2009; 49: 1695-1708
- Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome.J Clin Invest. 2009; 119: 305-314
- Activation of hepatocytes by extracellular heat shock protein 72.Am J Physiol Cell Physiol. 2008; 295: C514-C520
- Preparation of isolated rat liver cells.Methods Cell Biol. 1976; 13: 29-83
- Role of toll-like receptors in changes in gene expression and NF-κB activation in mouse hepatocytes stimulated with lipopolysaccharide.Infect Immun. 2002; 70: 3433-3442
- Carbon monoxide activates NF-κB via ROS generation and Akt pathways to protect against cell death of hepatocytes.Am J Physiol Gastrointest Liver Physiol. 2008; 295: G146-G152
- Nod1/RICK and TLR signaling regulate chemokine and antimicrobial innate immune responses in mesothelial cells.J Immunol. 2007; 179: 514-521
- Nuclear factor κB inactivation in the rat liver ameliorates short term total warm ischaemia/reperfusion injury.Gut. 2005; 54: 835-842
- Synergistic stimulation of human monocytes and dendritic cells by Toll-like receptor 4 and NOD1- and NOD2-activating agonists.Eur J Immunol. 2005; 35: 2459-2470
- Synergistic enhancement of Toll-like receptor responses by NOD1 activation.Eur J Immunol. 2005; 35: 2471-2476
- Peptidoglycan molecular requirements allowing detection by Nod1 and Nod2.J Biol Chem. 2003; 278: 41702-41708
- Nod1 acts as an intracellular receptor to stimulate chemokine production and neutrophil recruitment in vivo.J Exp Med. 2006; 203: 203-213
- Hypoxia-reoxygenation-induced chemokine transcription is not prevented by preconditioning or intermittent hypoxia, in mice hepatocytes.Transpl Int. 2005; 18: 444-452
- Nod1 and Nod2 induce CCL5/RANTES through the NF-κB pathway.Eur J Immunol. 2007; 37: 2499-2508
- Chemokine-directed immune cell infiltration in acute and chronic liver disease.Expert Rev Gastroenterol Hepatol. 2008; 2: 233-242
- CCR1 and CCR5 promote hepatic fibrosis in mice.J Clin Invest. 2009; 119: 1858-1870
- A major role for intestinal epithelial nucleotide oligomerization domain 1 (NOD1) in eliciting host bactericidal immune responses to Campylobacter jejuni.Cell Microbiol. 2007; 9: 2404-2416
- NOD2: a potential target for regulating liver injury.Lab Invest. 2008; 88: 318-327
Article info
Publication history
Published online: June 23, 2010
Accepted:
April 19,
2010
Received in revised form:
March 22,
2010
Received:
November 18,
2009
Identification
Copyright
© 2010 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
