期刊
INFLAMMATORY BOWEL DISEASES
卷 20, 期 9, 页码 1502-1515出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/MIB.0000000000000121
关键词
IL-17; TNF; susceptibility gene; Th17 cell; bispecific antibody; Crohn's disease; ulcerative colitis; ICAM1; FUT2; LTB; JAK2; CCL20; CXCL1; CXCL8
资金
- Else-Kroner-Fresenius-Stiftung [2010_EKES.32]
- Deutsche Forschungsgemeinschaft (DFG) [BR 1912/6-1, BE 4490/2-1]
Background: In contrast to anti-TNF-alpha antibodies, anti-IL-17A antibodies lacked clinical efficacy in a trial with patients suffering from Crohn's disease. We therefore analyzed how IL-17A modulates the inflammatory response elicited by TNF-alpha in intestinal epithelial cells (IEC). Methods: Target mRNA levels in IEC and colonic biopsies were assessed by RNA microarray and quantitative real-time PCR. Signaling pathways were analyzed using receptor neutralization and pharmacological inhibitors. Target protein levels were determined by immunoblotting. Results: Microarray analysis demonstrated that IL-17A alone is a weak inducer of gene expression in IEC (29 regulated transcripts), but significantly affected the TNF-alpha-induced expression of 547 genes, with strong amplification of proinflammatory chemokines and cytokines (>200-fold increase of CCL20, CXCL1, and CXCL8). Interestingly, IL-17A differentially modulated the TNF-alpha-induced expression of several inflammatory bowel disease susceptibility genes in IEC (increase of JAK2 mRNA, decrease of FUT2, ICAM1, and LTB mRNA). Negative regulation of ICAM-1 by IL-17A was verified on protein level. The significance of these findings is emphasized by inflamed lesions of patients with inflammatory bowel disease demonstrating significant correlations (P < 0.01, Rho, 0.57-0.85) for JAK2, ICAM1, and LTB mRNA with IL17A and TNF mRNA. Conclusions: Our study demonstrates the modulation of inflammatory bowel disease susceptibility gene mRNA in IEC as a novel important property of IL-17A. Given the weak impact of sole IL-17A stimulation on IEC target gene expression, our study provides an important explanation for the lack of clinical efficacy of sole IL-17A neutralization, but suggests a beneficial effect of combined IL-17A/TNF-alpha that is currently in clinical development.
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