Developmental control of the Nlrp6 inflammasome and a substrate, IL-18, in mammalian intestine.

Authors: Kempster, SL  Belteki, G  Forhead, AJ  Fowden, AL  Catalano, RD  Lam, BY  McFarlane, I  Charnock-Jones, DS  Smith, GC 
Citation: Kempster SL, etal., Am J Physiol Gastrointest Liver Physiol. 2010 Nov 18.
Pubmed: (View Article at PubMed) PMID:21088234
DOI: Full-text: DOI:10.1152/ajpgi.00397.2010

The inflammasome is a multiprotein complex whose formation is triggered when a NOD-like receptor binds a pathogen ligand resulting in activated Caspase-1, which converts certain interleukins (IL1beta, IL-18 and IL-33) to their active forms. There is currently no information on regulation of this system around the time of birth. We employed transcript profiling of fetal rat intestinal and lung RNA at embryonic day 16 (E16) and E20 with out of sample validation using quantitative RT-PCR. Transcript profiling and quantitative RT-PCR demonstrated that transcripts of core components of the NOD-like receptor Nlrp6 inflammasome (Nlrp6, Pycard, Caspase-1) and one of its substrates, IL-18, were increased at E20, compared with E16 in fetal intestine and not lung. Immunohistochemistry demonstrated increased Pycard in intestinal epithelium. Western blotting demonstrated that IL-18 was undetectable at E16; clearly detectable at E20 in its inactive form and detectable postnatally in both its inactive and active form. Dramatic up-regulation of IL-18 was also observed in the fetal sheep jejunum in late gestation (p=0.006). Transcription factor binding analysis of the rat array data revealed an over-representation of nuclear transcription factor binding sites peroxisome proliferator-activated receptor gamma and retinoid X receptor alpha and chicken ovalbumin upstream promoter transcription factor 1 in the region 1000bp upstream of the transcription start site. Rosiglitazone, a PPAR-gamma agonist, more than doubled levels of NLRP6 mRNA in human intestinal epithelial (Caco2) cells. These observations provide the first evidence, to our knowledge, linking activity of PPAR-gamma to expression of a NOD-like receptor and adds to a growing body of evidence linking pattern recognition receptors of the innate immune system and intestinal colonization.


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CRRD Object Information
CRRD ID: 4889157
Created: 2010-11-30
Species: All species
Last Modified: 2010-11-30
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.