Heterogeneity in the IL-13 Receptor Pathway and Activity in Active Ulcerative Colitis

Introduction: IL-13 has been shown to be elevated in ulcerative colitis (UC) and be pathogenic in animal models of UC.  However trials of anti-IL-13 antibodies or agents blocking IL-13 have shown efficacy only in subsets of patients.  We studied UC patients with active disease for heterogeneity in IL-13 activity and receptor expression to identify subsets of patients who could be more responsive to anti-IL-13 strategies. Methods: Whole endoscopic colon biopsies and isolated epithelial cells and LPMCs from from active(n=8) and remission(n=10) UC patients were studied. Epithelial cell SOCS-1 expression following in vitro IL-13 exposure and RT-PCR and RNASeq on RNA from un-stimulated cells were performed. Results: Active UC patients versus remission were significantly different by CRP (40.8mg/dL±17.6v1.8±0.6,p<0.03), Hgb (12.2g/dL±0.9v14.1±0.4,p<0.05), and Alb (3.4g/dL±0.3v4.2±0.1,p=0.02).  Active UC patients also expressed significantly more ALOX12 and IL13RA2, but had similar in vitro IL-13-induced epithelial cell SOCS1 and basal IL13RA1, tissue claudin-2 and eoxtaxin-3 expression.  In both active and remission patients IL-13-induced SOCS1 had significant inverse correlation with epithelial IL13RA1 expression (r²=0.63) and did not correlate with IL13RA2 expression.  When active UC patients were stratified by presence or absence of IL13RA2 expression, those patients positive for IL13RA2 had significantly more eotaxin-3 gene expression (11.3-fold±6.1v3.9±0.9,p<0.02).  This was not seen in remission UC patients. Conclusions: These data suggest that there are identifiable subsets of active UC patients that differ in local effects of IL-13.  The active UC patients with IL13RA2 and eotaxin-3 expression (both IL-13-onduced) may represent an IL-13-skewed inflammation that is more responsive to targeted anti-IL-13 agents.