Overexpression of the apoptosis inhibitor FLIP in T cells correlates with disease activity in multiple sclerosis

Semra, Y K; Seidi, Osheik; Sharief, Mohammed

doi:10.1016/s0165-5728(00)00443-4

Cited by 71 publications

(43 citation statements)

References 46 publications

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“…It is critical that excess activated T lymphocytes are eliminated to avoid formation of unwanted autoreactive or allergy promoting lymphocyte populations (57)(58)(59). Our results indicate that hyperthermia is an important determinant for appropriate apoptotic signaling in activated T lymphocytes.…”

Section: Discussionmentioning

confidence: 71%

“…The excess of activated T lymphocytes needs to be efficiently eliminated at the end of an immune response to avoid autoreactivity. Indeed, high quantities of c-FLIP and impaired lymphocyte apoptosis are associated with several cases of autoimmune diseases (57)(58)(59). Because the amount of c-FLIP is regulated both at the level of synthesis and degradation (27,60,61), changes in the intracellular c-FLIP expression provide an efficient and well-regulated mechanism for the T lymphocytes to modulate their susceptibility to apoptotic signaling.…”

Section: Fever-like Hyperthermia Controls T Lymphocyte Persistence Bymentioning

confidence: 99%

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Fever-Like Hyperthermia Controls T Lymphocyte Persistence by Inducing Degradation of Cellular FLIPshort

Meinander

Söderström

Kaunisto

et al. 2007

The Journal of Immunology

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Fever has a major impact on immune responses by modulating survival, proliferation, and endurance of lymphocytes. Lymphocyte persistence in turn is determined by the equilibrium between death and survival-promoting factors that regulate death receptor signaling in these cells. A potential integrator of death receptor signaling is the caspase-8 inhibitor c-FLIP, the expression of which is dynamically regulated, either rapidly induced or down-regulated. In this study, we show in activated primary human T lymphocytes that hyperthermia corresponding to fever triggered down-regulation of both c-FLIP-splicing variants, c-FLIPshort (c-FLIPS) and c-FLIPlong, with consequent sensitization to apoptosis mediated by CD95 (Fas/APO-1). The c-FLIP down-regulation and subsequent sensitization was specific for hyperthermic stress. Additionally, we show that the hyperthermia-mediated down-regulation was due to increased ubiquitination and proteasomal degradation of c-FLIPS, the stability of which we have shown to be regulated by its C-terminal splicing tail. Furthermore, the induced sensitivity to CD95 ligation was independent of heat shock protein 70, as thermotolerant cells, expressing substantially elevated levels of heat shock protein 70, were not rescued from the effect of hyperthermia-mediated c-FLIP down-regulation. Our findings indicate that fever significantly influences the rate of lymphocyte elimination through depletion of c-FLIPS. Such a general regulatory mechanism for lymphocyte removal has broad ramifications for fever-mediated regulation of immune responses.

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Section: Discussionmentioning

confidence: 71%

Section: Fever-like Hyperthermia Controls T Lymphocyte Persistence Bymentioning

confidence: 99%

Fever-Like Hyperthermia Controls T Lymphocyte Persistence by Inducing Degradation of Cellular FLIPshort

Meinander

Söderström

Kaunisto

et al. 2007

The Journal of Immunology

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“…The extended inflammatory reaction in the CNS was also visible in the periphery as a Th1 cytokine bias in the spleen, caused by an increased production of IFN-␥ and a concomitant decrease of IL-4. Despite previous reports suggesting that cellular overexpression of FLIP is a feature of clinically definite MS (43,44), the effect of FLIP overexpression in EAE models has never been evaluated before. We therefore tested the consequence of constitutive FLIP expression in the pathogenesis of MOG-induced EAE in DBA/1 mice.…”

Section: Discussionmentioning

confidence: 98%

“…This theory is interesting in view of recent data reporting overexpression of the long and short forms of c-FLIP in intrathecal lymphocytes from patients with MS (43). A specific up-regulation of these two isoforms in activated T cells from patients with clinically active MS, correlating with resistance to Fas-mediated apoptosis, has also been demonstrated (44).…”

Section: E Xperimental Autoimmune Encephalomyelitis (Eae)mentioning

confidence: 89%

Expression of the Long Form of Human FLIP by Retroviral Gene Transfer of Hemopoietic Stem Cells Exacerbates Experimental Autoimmune Encephalomyelitis

Djerbi

Abdul-Majid

Abedi‐Valugerdi

et al. 2003

The Journal of Immunology

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Subsidence of inflammation and clinical recovery in experimental autoimmune encephalomyelitis (EAE) is postulated to involve apoptosis of inflammatory cells. To test this concept, we examined the effects of overexpressing the long form of human FLICE-inhibitory protein, a potent inhibitor of death receptor-mediated apoptosis, in myelin oligodendrocyte glycoprotein-induced EAE in DBA/1 mice. We found that overexpression of the long form of human FLICE-inhibitory protein by retroviral gene transfer of hemopoietic stem cells led to a clinically more severe EAE in these mice compared with control mice receiving the retroviral vector alone. The exacerbated disease was evident by an enhanced and prolonged inflammatory reaction in the CNS of these animals compared with control mice. The acute phase of EAE was characterized by a massive infiltration of macrophages and granulocytes and a simultaneous increase in TNF-α production in the CNS. In the chronic phase of the disease, there was a prolonged inflammatory response in the form of persistent CD4+ T and B cells in the CNS and a peripheral Th1 cytokine bias caused by elevated levels of IFN-γ and reduced levels of IL-4 in the spleen. Our findings demonstrate that death receptor-mediated apoptosis can be important in the pathogenesis of EAE and further emphasize the need for effective apoptotic elimination of inflammatory cells to achieve disease remission.

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“…The expression of c-FLIP may dictate the pathological nature of human T cells because its expression is increased in T cells from patients with multiple sclerosis (MS) and Crohn's disease (39,40). Further, the effects of IL-1 and IL-6 on the resistance of human CD8 T cells to Fas-mediated AICD may augment the pathological nature of this cell type in autoimmune diseases and organ transplantation (41,42).…”

Section: Discussionmentioning

confidence: 99%

Inflammatory Cytokines Determine the Susceptibility of Human CD8 T Cells to Fas-mediated Activation-induced Cell Death through Modulation of FasL and c-FLIPS Expression

Rossum

Krall

Escalante

et al. 2011

Journal of Biological Chemistry

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Overexpression of the apoptosis inhibitor FLIP in T cells correlates with disease activity in multiple sclerosis

Cited by 71 publications

References 46 publications

Fever-Like Hyperthermia Controls T Lymphocyte Persistence by Inducing Degradation of Cellular FLIPshort

Fever-Like Hyperthermia Controls T Lymphocyte Persistence by Inducing Degradation of Cellular FLIPshort

Expression of the Long Form of Human FLIP by Retroviral Gene Transfer of Hemopoietic Stem Cells Exacerbates Experimental Autoimmune Encephalomyelitis

Inflammatory Cytokines Determine the Susceptibility of Human CD8 T Cells to Fas-mediated Activation-induced Cell Death through Modulation of FasL and c-FLIPS Expression

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