Genetic Association Analysis of the Functional c.714T>G Polymorphism and Mucosal Expression of Dectin-1 in Inflammatory Bowel Disease

Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
PLoS ONE (Impact Factor: 3.23). 11/2009; 4(11):e7818. DOI: 10.1371/journal.pone.0007818
Source: PubMed


Dectin-1 is a pattern recognition receptor (PRR) expressed by myeloid cells that specifically recognizes β-1,3 glucan, a polysaccharide and major component of the fungal cell wall. Upon activation, dectin-1 signaling converges, similar to NOD2, on the adaptor molecule CARD9 which is associated with inflammatory bowel disease (IBD). An early stop codon polymorphism (c.714T>G) in DECTIN-1 results in a loss-of-function (p.Y238X) and impaired cytokine responses, including TNF-α, interleukin (IL)-1β and IL-17 upon in vitro stimulation with Candida albicans or β-glucan. The aim of the present study was to test the hypothesis that the DECTIN-1 c.714T>G (p.Y238X) polymorphism is associated with lower disease susceptibility or severity in IBD and to investigate the level of dectin-1 expression in inflamed and non-inflamed colon tissue of IBD patients.

Download full-text


Available from: Ad A van Bodegraven
  • Source
    • "However, little is known about the role of dectin-1 in maintaining intestinal homeostasis. Dectin-1 is highly expressed in the intestine [25] and humans with CD have also been shown to have increased numbers of dectin-1 expressing inflammatory cells in the intestine compared with healthy individuals [26]. Together this implies that dectin-1 may play a role in intestinal immunity. "
    [Show abstract] [Hide abstract]
    ABSTRACT: It is believed that inflammatory bowel diseases (IBD) result from an imbalance in the intestinal immune response towards the luminal microbiome. Dectin-1 is a widely expressed pattern recognition receptor that recognizes fungi and upon recognition it mediates cytokine responses and skewing of the adaptive immune system. Hence, dectin-1 may be involved in the pathogenesis of IBD. We assessed the responses of dectin-1 deficient macrophages to the intestinal microbiota and determined the course of acute DSS and chronic Helicobacter hepaticus induced colitis in dectin-1 deficient mice. We show that the mouse intestinal microbiota contains fungi and the cytokine responses towards this microbiota were significantly reduced in dectin-1 deficient macrophages. However, in two different colitis models no significant differences in the course of inflammation were found in dectin-1 deficient mice compared to wild type mice. Together our data suggest that, although at the immune cell level there is a difference in response towards the intestinal flora in dectin-1 deficient macrophages, during intestinal inflammation this response seems to be redundant since dectin-1 deficiency in mice does not affect intestinal inflammation in experimental colitis.
    Full-text · Article · Apr 2012 · BMC Gastroenterology
  • Source
    • "CARD9 is a caspase recruitment-domain–containing signaling protein expressed in various tissues.10,11 It is closely associated with several inflammatory diseases, including tuberculosis, inflammatory bowel disease, tuberculosis, and ankylosing spondylitis.13,29,30 In CARD9−/− mice, stimulation of dendritic cells caused a marked decrease in the production of IL-2, -6, and -10, and TNF-α and decreased numbers of Th17 cells.31,32,33 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Angiotensin II (Ang II)-induced cardiac remodeling with the underlying mechanisms involving inflammation and fibrosis has been well documented. Cytosolic adaptor caspase recruitment domain 9 (CARD9) has been implicated in the innate immune response. We aimed to examine the role of CARD9 in inflammation and cardiac fibrosis induced by Ang II. Two-month-old CARD9-deficient (CARD9(-/-)) and wild-type (WT) male mice were infused with Ang II (1,500 ng/kg/min) or saline for 7 days. Heart sections were stained with hematoxylin and eosin and Masson trichrome and examined by immunohistochemistry; and activity and protein levels were measured in macrophages obtained from mice. WT mice with Ang II infusion showed a marked increase in CARD9(+) macrophages in the heart, but CARD9(-/-) mice showed significantly suppressed macrophage infiltration and expression of proinflammatory cytokines, including interleukin-1β (IL-1β) and connective tissue growth factor (CTGF). Importantly, Ang II-induced cardiac fibrosis (extracellular matrix and collagen I deposition) was diminished in CARD9(-/-) hearts, as was the expression of transforming growth factor-β (TGF-β) and level of myofibroblasts positive for α-smooth muscle actin (α-SMA). Furthermore, Ang II activation of nuclear factor-κB (NF-κB), JNK and p38 mitogen-activated protein kinases (MAPKs) in WT macrophages was reduced in CARD9(-/-) macrophages. CARD9 plays an important role in regulating cardiac inflammation and fibrosis in response to elevated Ang II.
    Full-text · Article · Mar 2011 · American Journal of Hypertension
  • [Show abstract] [Hide abstract]
    ABSTRACT: Innate control of fungal infection requires the specific recognition of invariant fungal molecular structures by a variety of innate immune receptors, including Toll-like receptors. In addition to the role in inducing protective immune responses, Toll-like receptor engagement may paradoxically favor fungal infections, by inducing inflammatory pathology and impairing antifungal immunity. Although the dissection of complex genetic traits modulating susceptibility to fungal infections is complex, the contribution of host genetics may hold the key to elucidating new risk factors for these severe, often fatal diseases. Understanding host-pathogen interactions at the innate immune interface will eventually lead to the development of new therapeutics and genetic markers in fungal infections.
    No preview · Article · Oct 2010 · Expert Review of Anti-infective Therapy
Show more