Session Title: Cytokines, Mediators, and Gene Regulation II
Session Type: Abstract Submissions (ACR)
Background/Purpose: Inhibition of IL-6 is used for treatment of rheumatoid arthritis and now being investigated as biologic therapy for a wide variety of autoimmune conditions, including systemic lupus erythematosus, spondyloarthritis, vasculitides, and inflammatory bowel disease. Many of these conditions are complicated by intestinal inflammation. Yet little is known about the role of IL-6 in the bowel. Animal models have suggested that IL-6 signaling protects intestinal epithelial cells from apoptosis during toxin mediated injury with oral dextran sodium sulfate and C. rodentium infection.
Methods: We have begun to investigate the role of IL-6 in the intestine using two in vivo models of intestinal disease. First, we utilized the dnKO murine model of spontaneous colitis. These mice are transgenic for a dominant negative Tgfbr2 on T cells and are deficient in the IL10rbgene; both of these signaling pathways contain genes with risk alleles for autoimmunity. Antibiotics can inhibit spontaneous colitis that develops in these mice, and cohousing with unmanipulated littermates leads to colitis within days. We then utilized a biopsy wound model in which a colonoscope is used to introduce forceps which biopsy the colonic mucosa and make a wound which can then be evaluated as the tissue repairs itself.
Results: We found that treatment of dnKO mice with an inhibitory antibody for IL-6 at the time of cohousing led to more severe colitis as observed by increased inflammatory infiltrates and crypt drop-out when compared to control antibody treated mice. Evaluation of the intestinal epithelium with BrdU staining demonstrated significantly increased epithelial proliferation in dnKO mice treated with control antibody but nearly absent staining in the anti-IL-6 treated mice. After biopsy wound injury of wild type mice, IL-6 levels peak early, within 24 hours, and decline to undetectable levels by day 6. Mice deficient for IL-6 demonstrate impaired intestinal wound healing due to a severe epithelial proliferative defect. By in situ hybridization, we identify intestinal epithelial cells and endothelial cells as significant producers of IL-6 in both models. In order to further define the mechanism by which IL-6 could be controlling intestinal epithelial proliferation and repair, we evaluated its role in primary 3D cultures of intestinal crypt organoids. In these cultures, cellular proliferation was significantly inhibited when the inflammatory cytokines TNF-α and IFN-γ were added. However, the addition of IL-6 to the cultures resulted in the restoration of cellular proliferation, even in the presence of TNF-α and IFN-γ.
Conclusion: These data demonstrate the importance of IL-6 for intestinal epithelial proliferation after injury. The absence of IL-6 early after injury in the intestine, such as the case when anti-IL-6 therapy is used, may lead to severe defects in healing, increasing the risk for adverse events.
N. A. Manieri,
N. P. Malvin,
T. S. Stappenbeck,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/anti-il-6-therapy-impairs-intestinal-repair-through-inhibition-of-epithelial-proliferation-after-injury/