The online version of this article (doi:10.1186/1476-9255-9-39) contains supplementary material, which is available to authorized users.
Cynthia R Willis, Audrey Seamons contributed equally to this work.
CRW, LN, CLS, JM, and GC were employed by Amgen, Inc. at the time the studies were completed. This work was sponsored by Amgen, Inc. LMP received funding from Amgen, Inc. for portions of the studies conducted at the University of Washington. AS, TB, PT, SP, and BMI declare that they have no competing interests.
CRW and AS designed, conducted, analyzed and interpreted data, prepared figures, drafted and revised the manuscript. JM, TB, LMP designed, analyzed and interpreted data, and edited the manuscript. PT performed histopathology analysis and interpretation, and edited the manuscript. LN designed, performed, and analyzed flow cytometry data. GC performed statistical analysis and interpretation and designed the heat maps. SP performed the in vivo portions of the studies and tissue processing. CLS analyzed serum antibody concentrations. BMI contributed to data interpretation and editing of the manuscript. All authors have read and approved this manuscript.
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.
We 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.
Treatment 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.
Results 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.
Additional file 1:Figure S1. Naïve and activated/memory T cells were reduced in MLN in H. bilis-infected Mdr1a−/− mice treated with anti-IL-7Rα M595. MLN were harvested from mice shown in Figure 1a and cells were stained with antibodies to identify T-cell subsets by flow cytometry. Cell numbers of MLN (A) naïve (CD44 -CD62Lhi), (B) activated/memory (CD44 +CD62L low) CD4 + T cells, (C) naïve (CD44 -), and (D) activated/memory (CD44 +) CD8 + T cells are shown. Significant differences are shown (ANOVA followed by Tukey’s post-test or multivariate t method. * p < 0.05, ** p < 0.001, *** p < 0. 0001). (PDF 43 KB)
Additional file 2:Figure S2. Circulating concentrations of H. bilis-specific antibodies were lower in infected Mdr1a−/− mice treated with anti-IL-7Rα M595. Serum was collected from mice shown in Figure 1a and analyzed for Hb-specific IgG2a by ELISA. Anti- Hb absorbance was determined by calculating the average absorbance of each sample minus the average absorbance of the control wells. Data represent the mean ± SEM for each treatment group at each dilution. For statistical calculations, the optical density of each sample was multiplied by the dilution factor, then the values obtained in the 500-, 5000-, and 50,000-fold dilution groups were summed. The two anti-IL-7Rα M595-treated groups were compared to the isotype control group by taking the rank transformation of the data and performing ANOVA with Dunnett’s post-test. * p < 0. 05, **p < 0. 01. (PDF 78 KB)
Additional file 3:Table S1. Expression of serum and colon explant proteins and colon mRNA that were altered with colitis and with anti-IL-7Rα M595 antibody treatment in Hb-infected Mdr1a-/- mice. (DOC 202 KB)12950_2012_264_MOESM3_ESM.doc
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- Interleukin-7 receptor blockade suppresses adaptive and innate inflammatory responses in experimental colitis
Cynthia R Willis
Piper M Treuting
Carole L Smith
Brian M Iritani
- BioMed Central
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