Abstract

The transcriptional repressor protein BCL6 has been implicated in the pathogenesis of non-Hodgkin?s lymphoma, but little is known about the normal function of BCL6. We have previously shown that the targeted disruption of the BCL6 gene leads to Th2-mediated inflammation, suggesting that BCL6 plays an important role in the regulation of T helper type 2 (Th2) subset differentiation. The cytokine IL-4 and the transcription factor STAT6 are critical mediators of Th2 differentiation. We have found that BCL6 regulates a novel pathway of Th2 differentiation that is independent of IL-4 and STAT6. Our hypothesis is that the cytokine IL-6 has a unique ability to induce Th2 differentiation via this IL-4/STAT6-independent pathway. In this proposal, we plan to use mouse genetic, cellular and molecular techniques to study the mechanisms by which BCL6 regulates this novel pathway of Th2 differentiation. These studies will provide important insights into normal Th2 differentiation, which may lead to new understanding of allergic diseases such as asthma. These studies will also provide insight into the function of BCL6, which may help the treatment of B cell lymphoma.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046410-02
Application #
6510933
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Adams, Ken
Project Start
2001-09-01
Project End
2006-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
2
Fiscal Year
2002
Total Cost
$335,250
Indirect Cost

  Institution

Name
Indiana University-Purdue University at Indianapolis
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202

  Publications

Kusam, Saritha; Munugalavadla, Veerendra; Sawant, Deepali et al. (2009) BCL6 cooperates with CD40 stimulation and loss of p53 function to rapidly transform primary B cells. Int J Cancer 125:977-81
Broxmeyer, Hal E; Sehra, Sarita; Cooper, Scott et al. (2007) Aberrant regulation of hematopoiesis by T cells in BAZF-deficient mice. Mol Cell Biol 27:5275-85
Wang, Zheng-Yu; Kusam, Saritha; Munugalavadla, Veerendra et al. (2006) Regulation of Th2 cytokine expression in NKT cells: unconventional use of Stat6, GATA-3, and NFAT2. J Immunol 176:880-8
Yu, Raymond Yick-Loi; Wang, Xing; Pixley, Fiona J et al. (2005) BCL-6 negatively regulates macrophage proliferation by suppressing autocrine IL-6 production. Blood 105:1777-84
Wang, Zheng-Yu; Sato, Hiroshi; Kusam, Saritha et al. (2005) Regulation of IL-10 gene expression in Th2 cells by Jun proteins. J Immunol 174:2098-105
Sehra, Sarita; Patel, Dipak; Kusam, Saritha et al. (2005) A role for caspases in controlling IL-4 expression in T cells. J Immunol 174:3440-6
Kusam, Saritha; Toney, Lisa M; Sato, Hiroshi et al. (2003) Inhibition of Th2 differentiation and GATA-3 expression by BCL-6. J Immunol 170:2435-41