Human Molecular Genetics Advance Access originally published online on June 15, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 16 1715-1725
DOI: 10.1093/hmg/ddh182
Human Molecular Genetics, Vol. 13, No. 16 © Oxford University Press 2004; all rights reserved
Regulation of IL-8 and IL-1ß expression in Crohn's disease associated NOD2/CARD15 mutations
1The Martin Boyer Laboratories, Gastroenterology Section, Department of Medicine and 2Department of Statistics, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA
Received March 30, 2004; Accepted June 1, 2004
Crohn's disease (CD) is a chronic inflammation affecting the gastrointestinal tract. Three mutations (Arg702Trp, Gly908Arg and 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 1ß (IL-1ß) 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 with 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 ulcerative colitis individuals, low-dose MDP and TNF
alone results in only modest IL-1ß protein induction. With MDP plus TNF, there is a synergistic induction of IL-1ß secretion. In Leu1007fsinsC homozygotes, there is a profound defect in IL-1ß secretion, despite marked induction of IL-1ß mRNA. These findings demonstrate post-transcriptional dependency on the NOD2/CARD15 pathway for IL-1ß 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.
* To whom correspondence should be addressed at: The University of Chicago, 5841 S. Maryland Avenue, MC6084, Chicago, IL 60637, USA. Tel: +1 7737025375; Fax: +1 7737022281; Email: jcho{at}medicine.bsd.uchicago.edu
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