We published our finding that a major activity of IL-7 was through destabilization of the cell cycle inhibitor p27kip1. This explained how IL-7 induced cell division in T cells. We published our findings concerning the role of the intracellular domain of IL-7 receptor. This showed that the intracellular domain of other cytokine receptors can mimic some functions of the IL-7 receptor in T and B cell development. However one unique function of IL-7 receptor is the induction of TCR gamma gene rearrangement. We published our findings that pharmacological treatment with IL-7 induces a broad hematological stimulation, including myelopoiesis and erythropoiesis. This showed beneficial effects of IL-7 treatment beyond the expected effects on lymphopoiesis. Although IL-7 is essential for normal T cell development and maintenance, it has not been determined which cells actually produce the IL-7 protein because it is below the level of detection by immunohistochemistry. We produced mice with a marker knocked into the IL-7 locus that permitted visualizing the producing cells. This showed an extensive reticular network of IL-7-containing processes in thymus and bone marrow and the study is submitted for publication. We showed that the development of regulatory T cells requires stimulation by either IL-7 or TSLP and have submitted that study for publication. For homeostatic survival, T cells require two signals, IL-7 and a weak stimulation from the antigen receptor. We showed that this two signal requirement is based on IL-7 stimulation greatly amplifying weak antigen receptor signals. IL-7 strongly activated Lck which in turn greatly enhanced Zap70 activation by the antigen receptor. As part of the new Cancer and Inflammation Program, we initiated a new project. The goal is to create an inhibitor of bowel inflammation that would stop inflammatory bowel disease (and subsequent colon cancer) without systemically blocking host defense. To block IL-7 selectively in the bowel, we engineered a soluble form of the IL-7 receptor (IL-7-Fc) to be expressed by the food bacterium, Lactococcus lactis. This will be given orally to mice, aiming to block bowel inflammation and colon cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC009287-23
Application #
7592606
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
23
Fiscal Year
2007
Total Cost
$904,000
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Wuest, Thomas Y; Willette-Brown, Jami; Durum, Scott K et al. (2008) The influence of IL-2 family cytokines on activation and function of naturally occurring regulatory T cells. J Leukoc Biol 84:973-80
Takase, Hiroshi; Yu, Cheng-Rong; Ham, Don-Il et al. (2006) Inflammatory processes triggered by TCR engagement or by local cytokine expression: differences in profiles of gene expression and infiltrating cell populations. J Leukoc Biol 80:538-45
Yao, Zhengju; Cui, Yongzhi; Watford, Wendy T et al. (2006) Stat5a/b are essential for normal lymphoid development and differentiation. Proc Natl Acad Sci U S A 103:1000-5
Li, Wen Qing; Jiang, Qiong; Aleem, Eiman et al. (2006) IL-7 promotes T cell proliferation through destabilization of p27Kip1. J Exp Med 203:573-82
Kittipatarin, C; Li, W Q; Bulavin, D V et al. (2006) Cell cycling through Cdc25A: transducer of cytokine proliferative signals. Cell Cycle 5:907-12
Khaled, Annette R; Bulavin, Dmitry V; Kittipatarin, Christina et al. (2005) Cytokine-driven cell cycling is mediated through Cdc25A. J Cell Biol 169:755-63
Leviton, Alan; Dammann, Olaf; Durum, Scott K (2005) The adaptive immune response in neonatal cerebral white matter damage. Ann Neurol 58:821-8
Jiang, Q; Li, W-Q; Aiello, F B et al. (2005) Retroviral transduction of IL-7Ralpha into IL-7Ralpha-/- bone marrow progenitors: correction of lymphoid deficiency and induction of neutrophilia. Gene Ther 12:1761-8
Jiang, Qiong; Li, Wen Qing; Hofmeister, Robert R et al. (2004) Distinct regions of the interleukin-7 receptor regulate different Bcl2 family members. Mol Cell Biol 24:6501-13
Ashktorab, H; Frank, S; Khaled, A R et al. (2004) Bax translocation and mitochondrial fragmentation induced by Helicobacter pylori. Gut 53:805-13

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