Gastroenterology

Gastroenterology

Volume 141, Issue 1, July 2011, Pages 208-216
Gastroenterology

Original Research
Basic and Translational—Alimentary Tract
Defective Leukocyte GM-CSF Receptor (CD116) Expression and Function in Inflammatory Bowel Disease

https://doi.org/10.1053/j.gastro.2011.03.060Get rights and content

Background & Aims

Inflammatory bowel disease (IBD) refers to 2 chronic inflammatory diseases of the intestine, ie, ulcerative colitis and Crohn's disease. IBD results from environmental factors (eg, bacterial antigens) triggering a dysregulated immune response in genetically predisposed hosts. Although the basis of IBD is incompletely understood, a number of recent studies have implicated defective innate immune responses in the pathogenesis of IBD. In this regard, there is much interest in therapies that activate innate immunity (eg, recombinant granulocyte-macrophage colony-stimulating factor).

Methods

In this study, we screened expression and function of circulating leukocyte granulocyte-macrophage colony-stimulating factor receptor (CD116) messenger RNA and surface protein in 52 IBD patients and 52 healthy controls.

Results

Our results show that both granulocyte and monocyte CD116 levels, but not CD114 or interleukin-3Rα, were significantly decreased in IBD compared to control (P < .001) and disease controls (irritable bowel syndrome; P < .001; rheumatoid arthritis; P < .025). IBD-associated CD116 repression was more prominent in patients with ulcerative colitis compared to Crohn's disease (P < .05), was independent of disease activity (P > .05), and was not influenced by current medications (P > .05). Receiver operating characteristic curve analysis revealed that leukocyte CD116 expression is a sensitive (85%) and specific (92%) biomarker for IBD. Moreover, granulocyte CD116-mediated function (phosphorylation of signal transducers and activators of transcription 3) paralleled decreased expression of CD116 in IBD granulocytes compared to control (P < .001).

Conclusions

These studies identify defective expression and function of CD116 as a distinguishing feature of IBD and implicate an associated defect in innate immune responses toward granulocyte-macrophage colony-stimulating factor.

Section snippets

Human Subjects

The institutional review board of the University of Colorado Denver approved all human studies. CD and UC patients were diagnosed using established criteria and CD phenotype per the Montreal criteria12 (see Table 1 for patient characteristics). Irritable bowel syndrome (IBS) patients were diagnosed by ROME III criteria.13 Rheumatoid arthritis patients were diagnosed based on criteria of the American College of Rheumatology.14 Medications were recorded at time of blood draws and the attending

Results

Initial studies were undertaken to define the levels of CD116 messenger RNA in IBD and control granulocytes. As shown in Figure 1A, real-time PCR analyses for CD116 were compared in 10 healthy controls and 10 patients with IBD. As can be seen, CD116 messenger RNA levels were decreased by as much as 65% ± 8% in IBD granulocytes (P < .001). Defective CD116 expression was evident in both UC and CD, but not in granulocytes from patients with IBS (Figure 1A). To examine the specificity of this

Discussion

Given the unknown etiology of IBD, there is significant interest in both new therapies and biomarkers to define and subdivide patient populations. GM-CSF has attracted attention of late as a therapy for disorders of innate immunity, including IBD.5 In this study, we sought to define whether specific differences existed in CD116 expression between IBD and healthy control patients. Results from the present studies show that decreased expression and function of CD116 is a distinguishing feature of

Acknowledgments

Drs Goldstein and Kominsky contributed equally to this work.

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    Conflicts of interest The authors disclose no conflicts.

    Funding This work was supported by National Institutes of Health grants R37-DK5018, RO1-HL60569, and by support from the Crohn's and Colitis Foundation of America.

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