title: Tumor-shed PGE(2) impairs IL2Rgammac-signaling to inhibit CD4 T cell survival: regulation by theaflavins.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Molecular Medicine, Bose Institute, P-1/12 CIT Scheme VIIM, Kolkata, India.
authors.forename: Sreya
authors.initials: S
authors.lastname: Chattopadhyay
authors.forename: Sankar
authors.initials: S
authors.lastname: Bhattacharyya
authors.forename: Baisakhi
authors.initials: B
authors.lastname: Saha
authors.forename: Juni
authors.initials: J
authors.lastname: Chakraborty
authors.forename: Suchismita
authors.initials: S
authors.lastname: Mohanty
authors.forename: Dewan Md
authors.initials: DM
authors.lastname: Sakib Hossain
authors.forename: Shuvomoy
authors.initials: S
authors.lastname: Banerjee
authors.forename: Kaushik
authors.initials: K
authors.lastname: Das
authors.forename: Gaurisankar
authors.initials: G
authors.lastname: Sa
authors.forename: Tanya
authors.initials: T
authors.lastname: Das
mesh_terms: D000328:Adult; D017209:Apoptosis; D044946:Biflavonoids / Q000737:chemistry*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002392:Catechin / Q000737:chemistry*; D002470:Cell Survival; D015232:Dinoprostone / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007107:Immune System; D053631:Interleukin Receptor Common gamma Subunit / Q000378:metabolism*; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D009369:Neoplasms / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D044946:Biflavonoids; C507941:IL2RG protein, human; D053631:Interleukin Receptor Common gamma Subunit; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; D025521:Tumor Suppressor Proteins; C056068:theaflavin; D002392:Catechin; D015232:Dinoprostone