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Innate Dysfunction Promotes Linear Growth Failure in Pediatric Crohn's Disease and Growth Hormone Resistance in Murine Ileitis§

D'Mello, Sharon MD1; Trauernicht, Anna MD1; Ryan, Anne MD1; Bonkowski, Erin BS1; Willson, Tara BS1,2; Trapnell, Bruce C. MD3; Frank, Stuart J. MD4; Kugasathan, Subra MD5; Denson, Lee A. MD1,2*

Inflammatory Bowel Diseases:
doi: 10.1002/ibd.21689
Original Article: Original Clinical Articles
Abstract

Background:: Growth failure remains a common complication of pediatric Crohn's disease (CD) and has been associated with small bowel involvement and need for surgery. We have reported that patients with elevated (≥1.6 μg/mL) granulocyte macrophage colony stimulating factor autoantibodies (GM‐CSF Ab) are more likely to experience complicated ileal disease requiring surgery. We hypothesized that concurrent GM‐CSF Ab and CARD15 risk allele carriage (C15+GMAb+) would be associated with growth failure in CD and growth hormone (GH) resistance in murine ileitis.

Methods:: We enrolled 229 pediatric CD patients at two sites and determined CARD15 genotype, serum GM‐CSF Ab, and GH binding protein (GHBP), and height (HTz) and weight (WTz) z‐scores at diagnosis. Ileitis was induced in card15‐deficient mice by GM‐CSF neutralization and nonsteroidal antiinflammatory drug (NSAID) exposure. Hepatic GH receptor (GHR) abundance and GH‐dependent Stat5 activation were determined by western blot and Igf‐I mRNA expression by real‐time polymerase chain reaction (PCR).

Results:: Mean (95% confidence interval [CI]) HTz at diagnosis was reduced to −0.48 (−4.2, 2.3) in C15+GMAb+patients, compared to −0.07 (−4.9, 3.4) in disease controls (P ≤ 0.05). Circulating GHBP, as a marker for tissue GHR abundance, was reduced in C15+GMAb+ patients. Hepatic GHR abundance, GH induction of Stat5 tyrosine phosphorylation, and Igf‐I mRNA expression were reduced in male card15‐deficient mice with ileitis due to GM‐CSF neutralization and NSAID exposure.

Conclusions:: Innate dysfunction due to concurrent genetic variation in CARD15 and neutralizing GM‐CSF Ab is associated with linear growth failure in pediatric CD, and hepatic GH resistance in murine ileitis. (Inflamm Bowel Dis 2011;)

Author Information

1Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, University of Cincinnati, Cincinnati, Ohio

2Department of Cancer and Cell Biology, University of Cincinnati, Cincinnati, Ohio

3Pulmonary Biology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, University of Cincinnati, Cincinnati, Ohio

4Department of Medicine, University of Alabama at Birmingham School of Medicine, and Medical Service, Birmingham VA Medical Center, Birmingham, Alabama

5Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia

*MLC 2010, 3333 Burnet Ave., Cincinnati, OH 45229

Email: lee.denson@cchmc.org

Received 29 December 2010; Accepted 19 January 2011

Published online 18 February 2011 in Wiley Online Library (wileyonlinelibrary.com).

§Supported by the Crohn's & Colitis Foundation of America through a generous gift from the Litwin Foundation, the Broad Medical Research Program, the Integrative Morphology core of the National Institutes of Health (NIH)‐supported Cincinnati Children's Hospital Research Foundation Digestive Health Center (1P30DK078392‐01), NIH grants R01 DK078683 (to LD.), DK068164 (to L.D.), and T32 DK007727 (to S.D., A.T.), and a VA Merit Review grant (to S.F.).

Additional Supporting Information may be found in the online version of this article.

© Crohn's & Colitis Foundation of America, Inc.

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