Genipin attenuates sepsis-induced immunosuppression through inhibition of T lymphocyte apoptosis.
Sepsis, a systemic inflammatory response to infection, initiates a complex immune response consisting of an early hyperinflammatory response and a subsequent hypoinflammatory response that impairs the removal of infectious organisms. The importance of sepsis-induced immunosuppression and its contribution to mortality has recently emerged. Apoptotic depletion of T lymphocytes is a critical cause of immunosuppression in the late phase of sepsis. Genipin is a major active compound of gardenia fruit that has anti-apoptotic and anti-microbial properties. This study investigated the mechanisms of action of genipin on immunosuppression in the late phase of sepsis. Mice received genipin (1, 2.5 and 5mg/kg, i.v.) at 0 (immediately) and 24h after cecal ligation and puncture (CLP). Twenty-six hours after CLP, the spleen and blood were collected. Genipin improved the survival rate compared to controls. CLP increased the levels of FADD, caspase-8 and caspase-3 protein expression, which were attenuated by genipin. Genipin increased the level of anti-apoptotic B-cell lymphoma-2 protein expression, while it decreased the level of pro-apoptotic phosphorylated-Bim protein expression in CLP. CLP decreased the CD4(+) and CD8(+) T cell population, while it increased the regulatory T cell (Treg) population and the level of cytotoxic T lymphocyte-associated antigen 4 protein expression on Treg. These changes were attenuated by genipin. The splenic levels of interferon-γ and interleukin (IL)-2 were reduced, while the levels of IL-4 and IL-10 increased after CLP. Genipin attenuated these alterations. These findings suggest that genipin reduces immunosuppression by inhibiting T lymphocyte apoptosis in the late phase of sepsis.
School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea. Electronic address: kimjs198@hotmail.com.
Joon-Sung
JS
Kim
School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea. Electronic address: starsojin@gmail.com.
So-Jin
SJ
Kim
School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea. Electronic address: sunmee@skku.edu.
Sun-Mee
SM
Lee
D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000009:adverse effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002432:Cecum / Q000601:surgery; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D032062:Gardenia / Q000276:immunology; D006801:Humans; D007165:Immunosuppression Therapy; D039823:Iridoids / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018805:Sepsis / Q000276:immunology / Q000628:therapy*; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D058408:Th1-Th2 Balance / Q000187:drug effects
D000276:Adjuvants, Immunologic; D016207:Cytokines; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D039823:Iridoids; D019253:Proto-Oncogene Proteins c-bcl-2; C007834:genipin; D053148:Caspase 3
Apoptosis; Genipin; Immunosuppression; Regulatory T cell; Sepsis; T helper 1/T helper 2 cytokine shift