%0 Journal Article
%T Tumor-Shed PGE2 Impairs IL2R¦Ãc-Signaling to Inhibit CD4+ T Cell Survival: Regulation by Theaflavins
%A Sreya Chattopadhyay
%A Sankar Bhattacharyya
%A Baisakhi Saha
%A Juni Chakraborty
%A Suchismita Mohanty
%A Dewan Md. Sakib Hossain
%A Shuvomoy Banerjee
%A Kaushik Das
%A Gaurisankar Sa
%A Tanya Das
%J PLOS ONE
%D 2009
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0007382
%X Background 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. Methodology/Principal Findings 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 ¦Ãc (IL2R¦Ãc)-mediated survival signaling in CD4+ T cells. Indeed, tumor-shed PGE2 down-regulates IL2R¦Ãc 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 IL2R¦Ãc/Jak-3/Stat-5A signaling in CD4+ T cells thereby protecting them from tumor-shed PGE2-induced apoptosis. Conclusions/Significance 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.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0007382