Lipocalin-2 Is a Disease Activity Marker in Inflammatory Bowel Disease Regulated by IL-17A, IL-22, and TNF-α and Modulated by IL23R Genotype Status. Issue 10 (October 2015)

• Record Type: Journal Article
• Authors: Stallhofer, Johannes; Friedrich, Matthias; Konrad-Zerna, Astrid; Wetzke, Martin; Lohse, Peter; Glas, Jürgen; Tillack-Schreiber, Cornelia; Schnitzler, Fabian; Beigel, Florian; Brand, Stephan
• Is Part Of: Inflammatory bowel diseases. Volume 21:Issue 10(2015:Oct.)
• Publication Date: 2015-10
• Subjects: biomarker -- Crohn's disease -- disease activity -- IL-17 -- IL-22 -- IL23R -- inflammatory bowel disease -- I-kappa-B-zeta -- lipocalin-2 -- neutrophil gelatinase–associated lipocalin -- 24p3 -- siderocalin -- Th17 cells -- TNF-α -- ulcerative colitis -- genetics -- cytokine; Inflammatory bowel diseases -- Periodicals; Colitis, Ulcerative -- Periodicals; Crohn Disease -- Periodicals; Inflammatory Bowel Diseases -- Periodicals; 616.344
• DOI: 10.1097/MIB.0000000000000515
• Languages: English
• ISSNs: 1078-0998

Abstract

Abstract : Background: Lipocalin-2 (LCN2) is a potent bacteriostatic protein. We aimed to investigate its role as a disease activity marker in patients with inflammatory bowel disease (IBD) and its induction by the Th17 cytokines IL-17A, IL-22, and TNF-α in colonic epithelial cells. Moreover, we analyzed the influence of IBD-associated IL23R alleles on LCN2 serum levels in IBD patients. Methods: LCN2 serum levels were determined in 131 IBD patients (71 with Crohn's disease [CD], 60 with ulcerative colitis [UC]) and 63 healthy controls. IBD patients were genotyped for 10 IBD-associated IL23R polymorphisms. LCN2 expression after stimulation with IL-17A, IL-22, and TNF-α was measured in human colonic epithelial cell lines. Results: A significant upregulation of serum LCN2 in active IBD (median [IQR], 36.84 [21.17–73.74] ng/mL; P = 0.01) compared with healthy controls (24.22 [17.76–35.25] ng/mL) was confined to active UC (42.21 [28.97–73.74] ng/mL; P = 0.0006). LCN2 proved to be a marker of UC disease activity (area under the curve 0.75, sensitivity 0.83, specificity 0.63; P = 0.0002). IL-17A showed a synergistic effect with IL-22 and TNF-α in inducing colonic epithelial expression of LCN2 and its essential transcription factor IKBZ . In CD, LCN2 concentrations were significantly modulated by IL23R genotype status with homozygous carriers of IBD risk–increasing alleles showing particularly low LCN2 levels. Conclusions: Serum LCN2 proves to be a biomarker of active UC. Lower LCN2 levels in CD patients carrying IBD risk–increasing IL23R variants may result from a restricted upregulation of LCN2 due to an impaired Th17 immune response. Abstract : Article first published online 07 August 2015.Supplemental Digital Content is Available in the Text.