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 Original paper

What was studied?

This original research study evaluated whether serum lipocalin-2 biomarker in ulcerative colitis can serve as a clinically useful indicator of inflammatory bowel disease (IBD) activity, and it investigated how lipocalin-2 (LCN2; also known as NGAL/siderocalin) is regulated by key Th17-pathway cytokines (IL-17A, IL-22) and TNF-α in human colonic epithelial cells. The authors also examined whether common IBD-associated IL23R genetic variants influence circulating LCN2 levels, linking host genetics and immune signaling to a measurable antimicrobial protein response. Methodologically, the work combined a patient cohort analysis of serum LCN2 with in vitro stimulation experiments in multiple human colonic epithelial cell lines to clarify mechanistic regulation (including transcriptional cofactor IKBZ/NFKBIZ) and to determine whether LCN2 behaves as a disease activity biomarker, particularly in ulcerative colitis.

Who was studied

The clinical cohort included 131 European Caucasian IBD patients recruited at a tertiary center in Munich, Germany: 71 with Crohn’s disease (CD) and 60 with ulcerative colitis (UC), plus 63 healthy controls without known inflammatory disease or anti-inflammatory drug use. Disease activity was assessed using CDAI for CD (active >150) and the Rachmilewitz clinical activity index for UC (active >3). Importantly, patients who had received anti–TNF-α therapy within 6 weeks were excluded, but other ongoing therapies (5-ASA, steroids, immunosuppressants, infliximab outside the window) were allowed, enabling evaluation of how treatment status related to serum LCN2. All IBD patients had IL23R genotyping available for 10 established risk/protective polymorphisms, allowing stratified analyses linking genotype to biomarker expression.

Most important findings

Serum LCN2 was significantly elevated in active IBD overall, but this signal was confined to active UC, where median LCN2 was 42.21 ng/mL versus 24.22 ng/mL in controls, and UC activity discrimination showed AUC ≈0.75 with a cutoff of 27.75 ng/mL, yielding sensitivity 0.83 and specificity ~0.64. LCN2 correlated strongly with CRP and WBC in both UC and CD, supporting its role as an inflammation-linked marker, yet CD patients did not show a clear activity-related increase—levels were heterogeneous and overlapped with remission and controls. Mechanistically, IL-17A synergized with IL-22 and especially TNF-α to induce epithelial LCN2 expression; the combination IL-17A+TNF-α produced the strongest induction across several cell lines, and cytokine stimulation also induced IKBZ, a key transcriptional cofactor for NF-κB–driven LCN2 transcription. A notable genetics finding was that in CD, IL23R genotype status modulated LCN2: carriers (particularly homozygotes) of CD risk–increasing IL23R alleles had lower serum LCN2, whereas protective alleles were associated with higher levels, suggesting a genetically constrained Th17/IL-23 antimicrobial response.

Key implications

Clinically, serum LCN2 appears to be a practical, blood-based marker for ulcerative colitis disease activity, with performance comparable to (and in sensitivity exceeding) standard systemic markers in this cohort, and it may be particularly valuable where repeated stool testing is undesirable. Biologically, the cytokine synergy data place LCN2 as an epithelial endpoint of IL-23/Th17/TNF signaling, a pathway tightly intertwined with host–microbe interactions, because LCN2 restricts bacterial iron acquisition. For microbiome-signature databases, LCN2 is best interpreted as a host antimicrobial response marker rather than a microbe-specific readout; nonetheless, the IL23R genotype effect in Crohn’s disease suggests that some patients may have genetically “blunted” LCN2 responses despite inflammation, which could confound biomarker interpretation and may correspond to altered microbial fitness dynamics under inflammation-driven iron limitation.

Citation

Stallhofer J, Friedrich M, Konrad-Zerna A, et al. 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. Inflamm Bowel Dis. 2015;21(10):2327-2340. doi:10.1097/MIB.0000000000000515