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Bortezomib Inhibits Expression of Immunosuppressive Cytokines IL‐10 and TGFβ in Cutaneous T Cell Lymphoma
Author(s) -
Chang Tzu-Pei,
Sanacora Shan,
Manna Subrata,
Singha Bipradeb,
Ramaswami Sitharam,
Vancurova Ivana
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.731.4
Subject(s) - bortezomib , cancer research , proteasome inhibitor , immune system , biology , b cell , chromatin immunoprecipitation , apoptosis , t cell , transcription factor , lymphoma , nf κb , immunology , multiple myeloma , gene expression , gene , promoter , inflammation , antibody , biochemistry
CTCL is characterized by the clonal expansion of helper T cells that release the immunosuppressive cytokines IL‐10 and TGFβ, thus suppressing the immune responses. NFκB is constitutively activated in CTCL and many other cancers, where it plays a crucial role in cell survival and resistance to apoptosis. While NFκB regulation of pro‐inflammatory and anti‐apoptotic genes has been studied extensively, the NFκB regulation of immunosuppressive genes is incompletely understood. Bortezomib is the 26S proteasome inhibitor, which has shown promising results in several forms of cancer, including CTCL. We have demonstrated that bortezomib inhibits NFκB activity and expression of anti‐apoptotic genes by inducing nuclear translocation of IκBα in CTCL Hut‐78 cells. In this study, we investigated whether bortezomib inhibits expression of IL‐10 and TGFβ in Hut‐78 cells, and we analyzed the underlying mechanisms. Our results show that bortezomib inhibits both IL‐10 and TGFβ expression in Hut‐78 cells. Chromatin immunoprecipitation analyses indicated that bortezomib inhibits NFκB recruitment to the promoter regions of IL‐10 and TGFβ genes. Since a variety of malignancies utilize the immunosuppressive cytokines IL‐10 and TGFβ to evade the immune surveillance and facilitate tumor growth, a better understanding of the mechanisms regulating transcription of these cytokines may lead to more effective cancer therapies. Funded by: NIH grants GM079581 and AI085497 to I.V.