Tumor-shed PGE(2) impairs IL2Rgammac-signaling to inhibit CD4 T cell survival: regulation by theaflavins

• Published in: PloS one Vol. 4; no. 10; p. e7382
• Main Authors: Chattopadhyay, Sreya, Bhattacharyya, Sankar, Saha, Baisakhi, Chakraborty, Juni, Mohanty, Suchismita, Sakib Hossain, Dewan Md, Banerjee, Shuvomoy, Das, Kaushik, Sa, Gaurisankar, Das, Tanya
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science (PLoS) 08.10.2009
• Subjects: Adult; Apoptosis; Biflavonoids - chemistry; Catechin - chemistry; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell Survival; Dinoprostone - metabolism; Gene Expression Regulation; Humans; Immune System; Interleukin Receptor Common gamma Subunit - metabolism; Jurkat Cells; Lymphocyte Activation; Neoplasms - metabolism; STAT5 Transcription Factor - metabolism; Transfection; Tumor Suppressor Proteins - metabolism
• ISSN: 1932-6203
• DOI: 10.1371/journal.pone.0007382

Many tumors are associated with decreased cellular immunity and elevated levels of prostaglandin E2 (PGE2), a known inhibitor of CD4+ T cell activation and inducer of type-2 cytokine bias. However, the role of this immunomodulator in the survival of T helper cells remained unclear. Since CD4+ T cells play critical roles in cell-mediated immunity, detail knowledge of the effect tumor-derived PGE2 might have on CD4+ T cell survival and the underlying mechanism may, therefore, help to overcome the overall immune deviation in cancer. By culturing purified human peripheral CD4+ T cells or Jurkat cells with spent media of theaflavin- or celecoxib-pre-treated MCF-7 cells, we show that tumor-shed PGE2 severely impairs interleukin 2 receptor gammac (IL2Rgammac)-mediated survival signaling in CD4+ T cells. Indeed, tumor-shed PGE2 down-regulates IL2Rgammac expression, reduces phosphorylation as well as activation of Janus kinase 3 (Jak-3)/signal transducer and activator of transcription 5 (Stat-5) and decreases Bcl-2/Bax ratio thereby leading to activation of intrinsic apoptotic pathway. Constitutively active Stat-5A (Stat-5A1 6) over-expression efficiently elevates Bcl-2 levels in CD4+ T cells and protects them from tumor-induced death while dominant-negative Stat-5A over-expression fails to do so, indicating the importance of Stat-5A-signaling in CD4+ T cell survival. Further support towards the involvement of PGE2 comes from the results that (a) purified synthetic PGE2 induces CD4+ T cell apoptosis, and (b) when knocked out by small interfering RNA, cyclooxygenase-2 (Cox-2)-defective tumor cells fail to initiate death. Interestingly, the entire phenomena could be reverted back by theaflavins that restore cytokine-dependent IL2Rgammac/Jak-3/Stat-5A signaling in CD4+ T cells thereby protecting them from tumor-shed PGE2-induced apoptosis. These data strongly suggest that tumor-shed PGE2 is an important factor leading to CD4+ T cell apoptosis during cancer and raise the possibility that theaflavins may have the potential as an effective immunorestorer in cancer-bearer.