Abstract
BackgroundMany 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 FindingsBy 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 γc (IL2Rγc)-mediated survival signaling in CD4+ T cells. Indeed, tumor-shed PGE2 down-regulates IL2Rγc 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 IL2Rγc/Jak-3/Stat-5A signaling in CD4+ T cells thereby protecting them from tumor-shed PGE2-induced apoptosis.Conclusions/SignificanceThese 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.
Highlights
Prostaglandins are lipid molecules regulating numerous processes including modulation of immune function [1,2,3]
prostaglandin E2 (PGE2) has been reported to down-regulate Janus kinase 3 (Jak-3) protein, which associates with IL2R, in T cells [26,27]
In the downstream, substantial activation of caspase-3 was observed in supernatant-treated CD4+ T cells. These results indicate a total impairment in interleukin 2 receptor cc (IL2Rcc) survival signaling in CD4+ T cells by tumor-secreted PGE2
Summary
Prostaglandins are lipid molecules regulating numerous processes including modulation of immune function [1,2,3]. Current paradigms suggest that CD4+ T cells play critical roles in the optimal induction and maintenance of clinically beneficial tumor immunity [7,8]. These cells prime CTL-mediated antitumor responses [9] by preventing activation-induced cell death and functioning as antigen-presenting cells for CTLs to preferentially generate immune memory cells [10,11]. PGE2 has been reported to down-regulate Jak-3 protein, which associates with IL2R, in T cells [26,27]. 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. 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, help to overcome the overall immune deviation in cancer
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
