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Interleukin-7 receptor blockade suppresses adaptive and innate inflammatory responses in experimental colitis

By Willis Cynthia R, Seamons Audrey, Maxwell Joe, Treuting Piper M, Nelson Laurel, Chen Guang, Phelps Susan, Smith Carole L, Brabb Thea, Iritani Brian M and Maggio-Price Lillian

Abstract

<p>Abstract</p> <p>Background</p> <p>Interleukin-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.</p> <p>Methods</p> <p>We examined the contribution of IL-7R on inflammation and disease development in two models of experimental colitis: <it>Helicobacter bilis</it> (<it>Hb</it>)-induced colitis in immune-sufficient <it>Mdr1a</it><sup>−/−</sup> mice and in T- and B-cell-deficient <it>Rag2</it><sup>−/−</sup> 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.</p> <p>Results</p> <p>Treatment of mice with an anti-IL-7R antibody was effective in reducing colitis in <it>Hb</it>-infected <it>Mdr1a</it><sup>−/−</sup> mice by reducing T-cell numbers as well as T-cell function. Down regulation of the innate immune response was also detected in <it>Hb</it>-infected <it>Mdr1a</it><sup>−/−</sup> mice treated with an anti-IL-7R antibody. In <it>Rag2</it><sup>−/−</sup> mice where colitis was triggered by <it>Hb</it>-infection, treatment with an anti-IL-7R antibody controlled innate inflammatory responses by reducing macrophage and dendritic cell numbers and their activity.</p> <p>Conclusions</p> <p>Results from our studies showed that inhibition of IL-7R successfully ameliorated inflammation and disease development in <it>Hb</it>-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.</p

Topics: IL-7R, Colitis, <it>Mdr1a</it><sup>−/−</sup> mice, <it>Rag2</it><sup>−/−</sup> mice, <it>Helicobacter bilis</it>, Pathology, RB1-214, Medicine, R, DOAJ:Pathology, DOAJ:Medicine (General), DOAJ:Health Sciences, Therapeutics. Pharmacology, RM1-950
Publisher: BioMed Central
Year: 2012
DOI identifier: 10.1186/1476-9255-9-39
OAI identifier: oai:doaj.org/article:23db1057d3b648d4bf53355b4a6502db
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