Human Molecular Genetics Advance Access published online on June 15, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh182
© 2004 by Oxford University Press
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1 The Martin Boyer Laboratories, Gastroenterology Section, Departments of Medicine, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637
* To whom correspondence should be addressed. E-mail: jcho{at}medicine.bsd.uchicago.edu.
Crohn's disease (CD) is a chronic inflammation affecting the gastrointestinal tract. Three mutations (Arg702Trp, Gly908Arg, Leu1007fsinsC) within the NOD2/CARD15 gene increase CD susceptibility. Here we define cytokine regulation in primary human mononuclear cells, with muramyl dipeptide (MDP), the minimal NOD2/CARD15 activating component of peptidoglycan. By microarray, MDP induces a broad array of transcripts, including interleukin 1
Article
Regulation of IL-8 and IL-1
expression in Crohn's disease associated NOD2/CARD15 mutations
2 Departments of Statistics, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637
3 The Martin Boyer Laboratories, Gastroenterology Section, Departments of Medicine, The University of Chicago, 5841 S. Maryland Avenue, MC6084, Chicago, IL 60637
Abstract 
(IL-1? and interleukin 8 (IL-8). Leu1007fsinsC homozygotes demonstrated decreased transcriptional response to MDP. Electromobility shift assay demonstrated that MDP-induced NF-
B activation is mediated via p50 and p65 subunits, but not RelB or c-Rel. In wild-type individuals, MDP induced IL-8 protein expression, with a greater response to high dose (1 µg/ml) compared to low dose (10 ng/ml) MDP. At low MDP doses, in all homozygotes, we observed no induction of IL-8 protein. With high doses of MDP, Leu1007fsinsC homozygotes showed no induction, modest induction of IL-8 protein was observed in Gly908Arg and Arg702Trp homozygotes, indicating varying MDP sensitivity of the CD-associated mutations. In wild-type healthy control, CD and UC individuals, low dose MDP and TNF
alone results in only modest IL-1 protein induction. With MDP plus TNF, there is a synergistic induction of IL-1 secretion. In Leu1007fsinsC homozygotes, there is a profound defect in IL-1 secretion??despite marked induction of IL-1 mRNA. These findings demonstrate post-transcriptional dependency on the NOD2/CARD15 pathway for IL-1 secretion with MDP and TNF treatment. Taken together, these studies suggest that a signaling defect of innate immunity to MDP may be an essential underlying defect in the pathogenesis of some CD patients.
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