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.
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.
*Department of Medicine II, Grosshadern, Ludwig-Maximilians-Universität (LMU), Munich, Germany; †Clinic for Preventive Dentistry and Parodontology, LMU Munich, Munich, Germany; ‡Clinic for Pediatric Pneumology and Neonatology, Hannover Medical School, Hannover, Germany; §Department of Clinical Chemistry, Grosshadern, LMU Munich, Munich, Germany; and ‖Institute of Human Genetics, RWTH Aachen University, Aachen, Germany.
Johannes
J
Stallhofer
Matthias
M
Friedrich
Astrid
A
Konrad-Zerna
Martin
M
Wetzke
Peter
P
Lohse
Jürgen
J
Glas
Cornelia
C
Tillack-Schreiber
Fabian
F
Schnitzler
Florian
F
Beigel
Stephan
S
Brand
D000209:Acute-Phase Proteins; D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood*; D003093:Colitis, Ulcerative / Q000097:blood / Q000235:genetics* / Q000276:immunology; D003106:Colon / Q000378:metabolism; D003424:Crohn Disease / Q000097:blood / Q000235:genetics* / Q000276:immunology; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D005838:Genotype; D064368:Healthy Volunteers; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D000071068:Lipocalin-2; D054834:Lipocalins / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000378:metabolism; D011110:Polymorphism, Genetic; D011518:Proto-Oncogene Proteins / Q000097:blood*; D018123:Receptors, Interleukin / Q000235:genetics* / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D055815:Young Adult; D000097043:Interleukin-22
D000209:Acute-Phase Proteins; D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D020672:I-kappa B Proteins; D020381:Interleukin-17; D007378:Interleukins; D000071068:Lipocalin-2; D054834:Lipocalins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D018123:Receptors, Interleukin; D014409:Tumor Necrosis Factor-alpha; D000097043:Interleukin-22; C508717:IL17A protein, human; C515500:IL23R protein, human; C489506:LCN2 protein, human; C417234:NFKBIZ protein, human