NF‐κB protects Behçet's disease T cells against CD95‐induced apoptosis up‐regulating antiapoptotic proteins

Todaro, Matilde; Zerilli, M; Triolo, G; Iovino, Flora; Patti, Mariella; Accardo-Palumbo, Antonina; Gaudio, Francesca Di; Turco, Maria Caterina; Petrella, Antonello; Maria, Ruggero De; Stassi, Giorgio

doi:10.1002/art.21145

Cited by 60 publications

(36 citation statements)

References 52 publications

(76 reference statements)

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“…2E). Behcet's disease resting T lymphocytes (36) and MCF-7 cells were used as positive controls. Thus, cFLIP L and PED/PEA-15 up-regulation in thyroid cancer cells may confer resistance to CD95-induced apoptosis.…”

Section: Il-4 and Il-10 In Thyroid Cancermentioning

confidence: 99%

Autocrine Production of Interleukin-4 and Interleukin-10 Is Required for Survival and Growth of Thyroid Cancer Cells

et al. 2006

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Although CD95 and its ligand are expressed in thyroid cancer, the tumor cell mass does not seem to be affected by such expression. We have recently shown that thyroid carcinomas produce interleukin (IL)-4 and IL-10, which promote resistance to chemotherapy through the up-regulation of Bcl-xL. Here, we show that freshly purified thyroid cancer cells were completely refractory to CD95-induced apoptosis despite the consistent expression of Fas-associated death domain and caspase-8. The analysis of potential molecules able to prevent caspase-8 activation in thyroid cancer cells revealed a remarkable up-regulation of cellular FLIP L (cFLIP L ) and PED/PEA-15, two antiapoptotic proteins whose exogenous expression in normal thyrocytes inhibited the death-inducing signaling complex of CD95. Additionally, small interfering RNA FLIP and PED antisense sensitized thyroid cancer cells to CD95-mediated apoptosis. Exposure of normal thyrocytes to IL-4 and IL-10 potently up-regulated cFLIP and PED/PEA-15, suggesting that these cytokines are responsible for thyroid cancer cell resistance to CD95 stimulation. Moreover, treatment with neutralizing antibodies against IL-4 and IL-10 or exogenous expression of suppressor of cytokine signaling-1 of thyroid cancer cells resulted in cFLIP and PED/PEA-15 downregulation and CD95 sensitization. More importantly, prolonged IL-4 and IL-10 neutralization induced cancer cell growth inhibition and apoptosis, which were prevented by blocking antibodies against CD95 ligand. Altogether, autocrine production of IL-4 and IL-10 neutralizes CD95-generated signals and allows survival and growth of thyroid cancer cells. Thus, IL-4 and IL-10 may represent key targets for the treatment of thyroid cancer. (Cancer Res 2006; 66(3): 1491-9)

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Section: Il-4 and Il-10 In Thyroid Cancermentioning

confidence: 99%

Autocrine Production of Interleukin-4 and Interleukin-10 Is Required for Survival and Growth of Thyroid Cancer Cells

et al. 2006

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“…These cytokines detected in patients with active disease point to a polarized Th1 immune response, as suggested by in vitro and in vivo studies of experimental autoimmune uveoretinitis [11]. We have also documented increased numbers of T lymphocytes expressing the gammadelta receptor that overproduce TNF in patients with active disease [12] and more recently a role of NF-kB in protecting T cells against CD95 induced apoptosis down-regulated by thalidomide, a TNF inhibiting agent [13].…”

Section: Introductionmentioning

confidence: 72%

One year study of efficacy and safety of infliximab in the treatment of patients with ocular and neurological Behçet’s disease refractory to standard immunosuppressive drugs

Giardina

Ferrante²,

Ciccia³

et al. 2009

Rheumatol Int

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The aim of the study was to assess the long-term eYcacy and safety of InXiximab therapy in the treatment of patients with Behçet's disease refractory to standard immunosuppressive agents. Twenty-one patients that did not respond to corticosteroids and to at least one immunosuppressant (cyclosporin, methotrexate, azathioprine, cyclophosphamide) for the presence of ocular and/or CNS involvement were enrolled. Eighteen patients completed the study up to 54 weeks. Stable doses of prednisone (<10 mg/day) were permitted, immunosuppressants were discontinued at least 4 weeks prior baseline visit. The patients received three infusions of 5 mg/kg InXiximab (at weeks 0, 2 and 6) and then infusions of 5 mg/kg InXiximab every 8 weeks. At each visit data on clinical symptoms, response to therapy and adverse events were collected. The primary outcome of interest was to assess the clinical eYcacy (total or partial recovery) of inXiximab. Secondary end points were to evaluate quality of life and to monitor the safety of the drug. Eighteen patients achieved a total remission. Two patients achieved a partial remission and relapsed after 3 months from discontinuation of therapy. InXiximab was well tolerated throughout the study. A case of non-Hodgkin lymphoma was observed within 6 months.Minor side eVects were headache, dizziness, tachycardia that regressed spontaneously and did not entail interruption. Anti-nuclear antibodies were not detected during the period of observation.

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“…[15][16][17] Accordingly, high expression of c-FLIP is generally observed in chronic inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, and Behçet disease. 18,[40][41][42] It was, however, also reported that NF-B RelA-deficient mouse embryonic fibroblasts do not differ in tumor necrosis factor (TNF)-induced c-FLIP expression compared with wild-type cells, suggesting that c-FLIP expression can occur independently of NF-B. 43 In contrast to CsA, we found that rocaglamide, which has been shown to inhibit NF-B as well as NFAT transcription factors, 25,26 impaired the expression of both c-FLIP long and c-FLIP short , suggesting that NF-B indeed contributes to c-FLIP gene regulation in T cells.…”

Section: Discussionmentioning

confidence: 99%

“…Inducible c-FLIP expression in peripheral T cells has primarily been linked to the nuclear factor-B (NF-B) signaling pathway [15][16][17][18] ; however, other transcription factor-binding sites do exist in the FLIP promoter. In addition, studies in various tumor cell lines have indicated a regulation of c-FLIP expression by the PI3K/Akt and Erk/MAP kinase pathway.…”

Section: Introductionmentioning

confidence: 99%

Up-regulation of c-FLIPshort by NFAT contributes to apoptosis resistance of short-term activated T cells

Ueffing

Schuster

Keil

et al. 2008

Blood

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IntroductionActivation of naive peripheral T cells by their cognate antigen results in induction of their proliferation and differentiation into T effector cells. These comprise CD4 ϩ T-helper cells and CD8 ϩ cytotoxic T cells, which in turn can induce immune responses by the secretion of cytokines, cell-cell interactions, or their ability to directly kill target cells. Importantly, despite high expression of death receptors such as CD95, effector T cells display an antiapoptotic phenotype allowing immune defense function and clearance of invading antigens. 1,2 Once the infection has been efficiently contained, these T cells become apoptosis-sensitive, leading to deletion of most cells and survival of a few memory T cells. 3,4 Apoptosis thus represents a tightly regulated process by which lymphocyte homeostasis is controlled and the emergence of autoreactive cells is prevented.Upon activation, T cells show a rapid up-regulation of antiapoptotic proteins. In addition to Bcl-x L , a strong increase in FLICEinhibitory proteins (FLIPs) is most prominent. 5-7 FLIPs inhibit death-receptor-mediated apoptosis by preventing the cleavage of death-inducing signaling complex (DISC)-associated procaspase-8 and Ϫ10 to the mature active enzymes, thereby blocking initiation of the extrinsic apoptosis cascade. 2,8 Three different isoforms of the cellular FLIP (c-FLIP) have been reported so far, namely c-FLIP long , c-FLIP short , and c-FLIP R , which are generated by alternative splicing. 2,5,9 All 3 isoforms comprise a tandem death effector motif (DED) that is crucial for their recruitment into the DISC. 10 Additionally, c-FLIP long contains an inactive caspase-like domain, whereas each of the 2 short isoforms, c-FLIP short and c-FLIP R , possesses a unique truncated C-terminus. For the latter ones only antiapoptotic functions have been described so far, whereas the role of c-FLIP L remains controversial. Next to its antiapoptotic abilities, low levels of c-FLIP long have also been shown to promote cell death by increasing the enzymatic activity of caspase-8. [11][12][13] In vitro studies with primary human T cells have shown that FLIP proteins, especially c-FLIP short , are highly up-regulated upon T-cell activation, which correlates with a protection against CD95-mediated apoptosis. 7,14 Conversely, treatment of activated T cells with the protein translation inhibitor cycloheximide reduced c-FLIP expression, without affecting Bcl-x L expression, and rendered the cells apoptosis sensitive. 7 Therefore, c-FLIP proteins are thought to play a central role in the protection of activated T cells.How c-FLIP expression in T cells is regulated at the molecular level is a matter of active debate. Inducible c-FLIP expression in peripheral T cells has primarily been linked to the nuclear factor-B (NF-B) signaling pathway [15][16][17][18] ; however, other transcription factor-binding sites do exist in the FLIP promoter. In addition, studies in various tumor cell lines have indicated a regulation of c-FLIP expression by the PI3K/Akt and Er...

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NF‐κB protects Behçet's disease T cells against CD95‐induced apoptosis up‐regulating antiapoptotic proteins

Cited by 60 publications

References 52 publications

Autocrine Production of Interleukin-4 and Interleukin-10 Is Required for Survival and Growth of Thyroid Cancer Cells

Autocrine Production of Interleukin-4 and Interleukin-10 Is Required for Survival and Growth of Thyroid Cancer Cells

One year study of efficacy and safety of infliximab in the treatment of patients with ocular and neurological Behçet’s disease refractory to standard immunosuppressive drugs

Up-regulation of c-FLIPshort by NFAT contributes to apoptosis resistance of short-term activated T cells

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