Abstract
BackgroundInterleukin-7 (IL-7) acts primarily on T cells to promote their differentiation, survival, and homeostasis. Under disease conditions, IL-7 mediates inflammation through several mechanisms and cell types. In humans, IL-7 and its receptor (IL-7R) are increased in diseases characterized by inflammation such as atherosclerosis, rheumatoid arthritis, psoriasis, multiple sclerosis, and inflammatory bowel disease. In mice, overexpression of IL-7 results in chronic colitis, and T-cell adoptive transfer studies suggest that memory T cells expressing high amounts of IL-7R drive colitis and are maintained and expanded with IL-7. The studies presented here were undertaken to better understand the contribution of IL-7R in inflammatory bowel disease in which colitis was induced with a bacterial trigger rather than with adoptive transfer.MethodsWe examined the contribution of IL-7R on inflammation and disease development in two models of experimental colitis: Helicobacter bilis (Hb)-induced colitis in immune-sufficient Mdr1a−/− mice and in T- and B-cell-deficient Rag2−/− mice. We used pharmacological blockade of IL-7R to understand the mechanisms involved in IL-7R-mediated inflammatory bowel disease by analyzing immune cell profiles, circulating and colon proteins, and colon gene expression.ResultsTreatment of mice with an anti-IL-7R antibody was effective in reducing colitis in Hb-infected Mdr1a−/− mice by reducing T-cell numbers as well as T-cell function. Down regulation of the innate immune response was also detected in Hb-infected Mdr1a−/− mice treated with an anti-IL-7R antibody. In Rag2−/− mice where colitis was triggered by Hb-infection, treatment with an anti-IL-7R antibody controlled innate inflammatory responses by reducing macrophage and dendritic cell numbers and their activity.ConclusionsResults from our studies showed that inhibition of IL-7R successfully ameliorated inflammation and disease development in Hb-infected mice by controlling the expansion of multiple leukocyte populations, as well as the activity of these immune cells. Our findings demonstrate an important function of IL-7R-driven immunity in experimental colitis and indicate that the therapeutic efficacy of IL-7R blockade involves affecting both adaptive and innate immunity.
Highlights
Interleukin-7 (IL-7) acts primarily on T cells to promote their differentiation, survival, and homeostasis
Our findings demonstrate an important function of IL-7 receptor (IL-7R)-driven immunity in experimental colitis involving both adaptive and innate immunity
Blockade of IL-7Rα ameliorated Helicobacter bilis (Hb)-induced colitis in Mdr1a−/− mice Mdr1a−/− mice develop colitis when infected with certain enteric helicobacter species [11]
Summary
Interleukin-7 (IL-7) acts primarily on T cells to promote their differentiation, survival, and homeostasis. Experimental studies in mice have revealed that a combination of genetic factors, diet, and immune responses to microbial organisms can contribute to IBD susceptibility In both humans and mouse models, several lines of evidence suggest a significant role for IL-7 in inflammatory diseases, including IBD. Adoptive transfer studies in these mice suggest that the colitogenic T cells are primarily memory CD4+ cells which express high IL-7Rα and are maintained and expanded with IL-7 [9,10], indicating that IL-7 signaling is important in IBD pathogenesis. In an adoptive T-celltransfer model of colitis, Yamazaki and colleagues successfully treated ongoing colitis using a saporinconjugated anti-IL-7Rα antibody, selectively eliminating lamina propria lymphocytes (LPL) with high expression of IL-7R [10] These and other studies suggest that therapies interfering with IL-7R signaling could abrogate intestinal inflammation in IBD
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