Activation‐induced cell death of human melanoma specific cytotoxic T lymphocytes is mediated by apoptosis‐inducing factor

Chhabra, Arvind; Mehrotra, Shikhar; Chakraborty, Nitya G.; Dorsky, David I.; Mukherji, Bijay

doi:10.1002/eji.200636550

Cited by 25 publications

(32 citation statements)

References 28 publications

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“…For an effective cancer immunotherapy, generation of a robust and strong CTL response against tumor-associated antigens in vivo by DC based active immunization or in-vitro for the purpose of adoptive immunotherapy is critical [28][29][30][31]. Various laboratories including our`s have utilized different strategies, to achieve a stronger and long lasting CTL response against cancer antigens [2,23,26,27,30,32]. Among various approaches we have employed include improving antigen delivery and processing conditions in DC [23] and interfering with the activation induced cell death (AICD) in the expanded CTL to sustain the CTL response longer [23,26].…”

Section: Discussionmentioning

confidence: 99%

“…CTL generation experiments were essentially performed as described previously, with minor modification [23,24,26]. Two days post siRNA treatment, DC were matured by overnight treatment with LPS and IFN-γ as described previously [24].…”

Section: In-vitro Cytotoxic T Lymphoctes (Ctl) Generation Protocolmentioning

confidence: 99%

“…Adherent blood monocytes grown in GM-CSF and IL-4 were used as immature DC and when needed, they were further matured in LPS and interferon gamma treatment, a well established and routinely reported method for DC maturation [23,24,26]. Immature DC expressed lower levels of MHC class I molecules and CD80 & CD86 co-stimulatory molecules and these molecules were up regulated upon maturation (Fig.…”

Section: Optimization Of Sirna Delivery Conditions In DCmentioning

confidence: 99%

“…In order to check the immunogenic potential of IL-10 silenced DC, we used these DC to generate a tetramer epitope specific CTL response in our in-vitro CTL activation model against the human melanoma associated antigenic epitope, MART-1 27−35 [23,24,26]. As shown in Fig.…”

Section: Il-10 Silenced DC Generates a Stronger Ctl Response Against mentioning

confidence: 99%

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Silencing of endogenous IL-10 in human dendritic cells leads to the generation of an improved CTL response against human melanoma associated antigenic epitope, MART-127–35

Chhabra

Chakraborty

Mukherji

2008

Clinical Immunology

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Dendritic cells (DC) present antigenic epitopes to and activate T cells. They also polarize the ensuing T cell response to Th1 or Th2 type response, depending on their cytokine production profile. For example, IL-12 producing DC generate Th1 type T cell response whereas IL-10 producing DC is usually tolerogenic. Different strategies --such as the use of cytokines and anti-cytokine antibodies, dominant negative forms of protein, anti-sense RNA etc. --have been employed to influence the cytokine synthetic profile of DC as well as to make DC more immunogenic. Utilizing GFP expressing recombinant adenoviruses in association with lipid-mediated transfection of siRNA, we have silenced the endogenous IL-10 gene in DC. We show that IL-10 gene silenced DC produce more IL-12 and also generates a better cytolytic T cell response against the human melanoma associated epitope, MART-1 27−35 , in-vitro. We also show that the GFP expressing adenoviral vector can be used to optimize the parameters for siRNA delivery in primary cells and show that RNA interference methodology can efficiently knock-down virus encoded genes transcribed at very high multiplicity of infection in DC.

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Section: Discussionmentioning

confidence: 99%

Section: In-vitro Cytotoxic T Lymphoctes (Ctl) Generation Protocolmentioning

confidence: 99%

Section: Optimization Of Sirna Delivery Conditions In DCmentioning

confidence: 99%

Section: Il-10 Silenced DC Generates a Stronger Ctl Response Against mentioning

confidence: 99%

See 2 more Smart Citations

Silencing of endogenous IL-10 in human dendritic cells leads to the generation of an improved CTL response against human melanoma associated antigenic epitope, MART-127–35

Chhabra

Chakraborty

Mukherji

2008

Clinical Immunology

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“…24). Once in the nucleus, AIF can lead to large-scale DNA fragmentation and chromatin condensation (25,26) in a caspase-independent manner (for review, ref. 27).…”

Section: Introductionmentioning

confidence: 99%

The Human Host Defense Peptide LL-37 Induces Apoptosis in a Calpain- and Apoptosis-Inducing Factor–Dependent Manner Involving Bax Activity

Mader

Mookherjee

Hancock

et al. 2009

Molecular Cancer Research

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LL-37 is a human cationic host defense peptide (antimicrobial peptide) belonging to the cathelicidin family of peptides. In this study, LL-37 was shown to kill Jurkat T leukemia cells via apoptosis. A loss of mitochondrial membrane potential, DNA fragmentation, and phosphatidylserine externalization were detected following LL-37 exposure, whereas apoptosis was independent of caspase family members. The specific apoptotic pathway induced by LL-37 was defined through the utilization of Jurkat cells modified to express antiapoptotic proteins, as well as cells deficient in various proteins associated with apoptosis. Of interest, both Bcl-2-overexpressing cells and cells deficient in Bax and Bak proteins displayed a significant reduction in LL-37-induced apoptosis. In addition, Jurkat cells modified in the Fas receptor-associated pathway showed no reduction in apoptosis when exposed to LL-37. Analysis of the involvement of apoptosis-inducing factor (AIF) in LL-37-mediated apoptosis revealed that AIF transferred from the mitochondria to the nucleus of cells exposed to LL-37, where it may lead to large-scale DNA fragmentation and chromatin condensation. AIF knockdown analysis resulted in LL-37-resistant cells. This suggests that AIF is mandatory in LL-37-mediated killing. Lastly, chelation or inhibition of Ca 2+ or calpains inhibited LL-37-mediated killing. Further analysis revealed that calpains were required for LL-37-mediated Bax translocation to mitochondria. Together, these data show that LL-37-induced apoptosis is mediated via the mitochondria-associated pathway in a caspase-independent and calpain-and AIF-dependent manner that involves Bax activation and translocation to mitochondria. (Mol Cancer Res 2009;7(5):689-702)

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Abnormality of maternal‐to‐embryonic transition contributes to MEHP‐induced mouse 2‐cell block

Chu

Shen

et al. 2012

Journal Cellular Physiology

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Mono (2-ethylhexyl) phthalate (MEHP), an environmental contaminant, is known to cause many serious diseases, especially in reproductive system. However, little is known about the effect of MEHP on preimplantation embryo development. In this study, we found that the development of mouse 2-cell embryo was blocked by 10(-3) M MEHP. A significant increase in the level of reactive oxygen species (ROS) was observed in arrested 2-cell embryo following 10(-3) M MEHP treatment for 24 h. However, antioxidants, catalase (CAT), and superoxide dismutase (SOD), reduced intracellular ROS and protected MEHP-exposed embryos from death but failed to return the arrested embryos. Further experiments demonstrated that the level of apoptosis was not altered in live arrested 2-cell embryo and increased in dead arrested 2-cell embryo after MEHP treatment, which implied that ROS and apoptosis were not related with 2-cell block. During analysis of the indicators of embryonic genome activation (EGA) initiation (Hsc70, MuERV-L, Hsp70.1, eIF-1A, and Zscan4) and maternal-effect genes (OCT4 and SOX2), we found that MEHP treatment could significantly decline Hsc70, MuERV-L mRNA level and SOX2 protein level, and markedly enhance Hsp70.1, eIF-1A, Zscan4 mRNA level, and OCT4 protein level at 2-cell to 4-cell stage. Supplementation of CAT and SOD did not reverse the expression tendency of EGA related genes. Collectively, this study demonstrates for the first time that MEHP-induced 2-cell block is mediated by the failure of EGA onset and maternal-effect genes, not oxidative stress and apoptosis.

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Activation‐induced cell death of human melanoma specific cytotoxic T lymphocytes is mediated by apoptosis‐inducing factor

Cited by 25 publications

References 28 publications

Silencing of endogenous IL-10 in human dendritic cells leads to the generation of an improved CTL response against human melanoma associated antigenic epitope, MART-127–35

Silencing of endogenous IL-10 in human dendritic cells leads to the generation of an improved CTL response against human melanoma associated antigenic epitope, MART-127–35

The Human Host Defense Peptide LL-37 Induces Apoptosis in a Calpain- and Apoptosis-Inducing Factor–Dependent Manner Involving Bax Activity

Abnormality of maternal‐to‐embryonic transition contributes to MEHP‐induced mouse 2‐cell block

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