Balance Between Survivin, a Key Member of the Apoptosis
Balance Between Survivin, a Key Member of the Apoptosis
Rheumatoid arthritis (RA) is a highly heterogeneous disease with respect to its joint destructivity. The reasons underlying this heterogeneity are unknown. Deficient apoptosis in rheumatoid synovial tissue has been recently demonstrated. We have therefore decided to study the synovial expression of survivin, a key member of the apoptosis inhibitor family. The levels of survivin and antibodies against survivin were assessed by an ELISA in matched blood and synovial fluid samples collected from 131 RA patients. Results were related to joint erosivity at the time of sampling. Monocytes were transfected with survivin anti-sense oligonucleotides and were assessed for their ability to produce inflammatory cytokines. Survivin levels were significantly higher in patients with destructive disease as compared with in RA patients displaying a non-erosive disease. High survivin levels were an independent prognostic parameter for erosive RA. In contrast, high levels of antibodies against survivin were found in patients with non-erosive RA, and were negatively related to erosivity. Survivin levels in RA patients were influenced by treatment, being significantly lower among patients treated with disease-modifying anti-rheumatic drugs. Specific suppression of survivin mRNA resulted in downregulation of IL-6 production. We conclude that survivin determines the erosive course of RA, whereas survivin antibodies lead to a less aggressive course of the disease. These findings together with decreased survivin levels upon disease-modifying anti-rheumatic drug treatment, and the downregulation of inflammatory response using survivin anti-sense oligonucleotides, suggest that extracellular survivin expression mediates the erosive course of joint disease whereas autoimmune responses to the same molecule, manifested as survivin targeting antibodies, mediate protection.
Rheumatoid arthritis (RA) is an inflammatory joint disease characterized by hyperplasia of synovial tissue and pannus formation growing invasively into the cartilage, followed by cartilage and bone destruction. Analyses of hyperplastic synovial tissues of patients with RA reveal features of transformed long-living cells such as the presence of somatic mutations, expression of oncogenes, and resistance to apoptosis. Resistance to apoptosis further contributes to synovial hyperplasia and is closely linked to the invasive phenotype of synovial fibroblasts.
Apoptosis is a tightly regulated process of elimination of aged cells without disrupting cellular integrity (reviewed in). Apoptosis may be initiated by extracellular stimuli through activation of death receptors on the cell surface, and intracellularly by the release of mitochondrial cytochrome c into the cytoplasm. Both pathways induce expression of apoptosis genes and activation of the caspase cascade, resulting in DNA fragmentation. The apoptosis signals are abrogated by the family of apoptosis-inhibiting proteins (IAPs).
A number of disturbances in the apoptosis machinery have been pointed out in RA patients. Fibroblasts from RA synovia are relatively resistant to apoptosis induced by extracellular Fas stimulation. Moreover, co-culture of synovial fibroblasts from RA joints with T cells and B cells induces anergy of lymphocytes. Increased levels of soluble Fas in RA synovial fluid have been suggested as one possible explanation for this fact. Indeed, administration of antagonistic anti-Fas antibodies or of Fas ligand has been shown effective in abrogation of arthritis in animal models. Resistance to Fas-induced apoptosis in RA synovium correlates with a markedly increased expression of sentrin-1. Sentrin-1/SUMO is a molecule whose binding to a protein results in the prevention of ubiquitin-related processing and degradation of that protein. Sentrin-mediated protection has been shown for such proteins as p53 and IkBa. Upregulation of anti-apoptotic molecules belonging to the Bcl family and of the caspase-8 inhibitor FLIP has been repeatedly reported in RA. Inhibited apoptosis has been shown to contribute to the pathogenesis of experimental arthritis.
Survivin is a 142-amino-acid protein that belongs to the IAP family, and it inhibits the activity of caspase 3, caspase 7, and caspase 9, but not of the upstream initiator protease caspase 8. Survivin can thereby downregulate, directly or indirectly, both death-receptor-mediated and mitochondria-mediated pathways of apoptosis. Survivin has been also suggested to regulate cell division during mitosis. Indeed, survivin is the only one of IAPs that is tightly connected to the cell cycle being upregulated in the G2 /M phase. Inside the dividing cell, survivin is found incorporated in centrosomes and mitotic spindles, and relocates to midbodies in the late telophase. Disruption of survivin function by negative mutation or by introduction of anti-sense oligonucleotides results in a cell-division defect. Survivin is abundantly expressed in all the most common human cancers and in transformed cell lines, while most normal differentiated adult tissues do not express this molecule. A few adult tissues reported to express survivin include the spleen, the testes, the thymi, the placentas, and the colonic crypts.
In the present study we demonstrate high levels of the anti-apoptotic protein survivin extracellularly in plasma and synovial fluid of patients with RA. In all the cases but one, high levels of survivin were associated with the erosive type of joint disease. Moreover, it is demonstrated that autoantibody responses to survivin led to a more benign (non-erosive) course of RA. The latter finding may have potential therapeutic consequences.
Rheumatoid arthritis (RA) is a highly heterogeneous disease with respect to its joint destructivity. The reasons underlying this heterogeneity are unknown. Deficient apoptosis in rheumatoid synovial tissue has been recently demonstrated. We have therefore decided to study the synovial expression of survivin, a key member of the apoptosis inhibitor family. The levels of survivin and antibodies against survivin were assessed by an ELISA in matched blood and synovial fluid samples collected from 131 RA patients. Results were related to joint erosivity at the time of sampling. Monocytes were transfected with survivin anti-sense oligonucleotides and were assessed for their ability to produce inflammatory cytokines. Survivin levels were significantly higher in patients with destructive disease as compared with in RA patients displaying a non-erosive disease. High survivin levels were an independent prognostic parameter for erosive RA. In contrast, high levels of antibodies against survivin were found in patients with non-erosive RA, and were negatively related to erosivity. Survivin levels in RA patients were influenced by treatment, being significantly lower among patients treated with disease-modifying anti-rheumatic drugs. Specific suppression of survivin mRNA resulted in downregulation of IL-6 production. We conclude that survivin determines the erosive course of RA, whereas survivin antibodies lead to a less aggressive course of the disease. These findings together with decreased survivin levels upon disease-modifying anti-rheumatic drug treatment, and the downregulation of inflammatory response using survivin anti-sense oligonucleotides, suggest that extracellular survivin expression mediates the erosive course of joint disease whereas autoimmune responses to the same molecule, manifested as survivin targeting antibodies, mediate protection.
Rheumatoid arthritis (RA) is an inflammatory joint disease characterized by hyperplasia of synovial tissue and pannus formation growing invasively into the cartilage, followed by cartilage and bone destruction. Analyses of hyperplastic synovial tissues of patients with RA reveal features of transformed long-living cells such as the presence of somatic mutations, expression of oncogenes, and resistance to apoptosis. Resistance to apoptosis further contributes to synovial hyperplasia and is closely linked to the invasive phenotype of synovial fibroblasts.
Apoptosis is a tightly regulated process of elimination of aged cells without disrupting cellular integrity (reviewed in). Apoptosis may be initiated by extracellular stimuli through activation of death receptors on the cell surface, and intracellularly by the release of mitochondrial cytochrome c into the cytoplasm. Both pathways induce expression of apoptosis genes and activation of the caspase cascade, resulting in DNA fragmentation. The apoptosis signals are abrogated by the family of apoptosis-inhibiting proteins (IAPs).
A number of disturbances in the apoptosis machinery have been pointed out in RA patients. Fibroblasts from RA synovia are relatively resistant to apoptosis induced by extracellular Fas stimulation. Moreover, co-culture of synovial fibroblasts from RA joints with T cells and B cells induces anergy of lymphocytes. Increased levels of soluble Fas in RA synovial fluid have been suggested as one possible explanation for this fact. Indeed, administration of antagonistic anti-Fas antibodies or of Fas ligand has been shown effective in abrogation of arthritis in animal models. Resistance to Fas-induced apoptosis in RA synovium correlates with a markedly increased expression of sentrin-1. Sentrin-1/SUMO is a molecule whose binding to a protein results in the prevention of ubiquitin-related processing and degradation of that protein. Sentrin-mediated protection has been shown for such proteins as p53 and IkBa. Upregulation of anti-apoptotic molecules belonging to the Bcl family and of the caspase-8 inhibitor FLIP has been repeatedly reported in RA. Inhibited apoptosis has been shown to contribute to the pathogenesis of experimental arthritis.
Survivin is a 142-amino-acid protein that belongs to the IAP family, and it inhibits the activity of caspase 3, caspase 7, and caspase 9, but not of the upstream initiator protease caspase 8. Survivin can thereby downregulate, directly or indirectly, both death-receptor-mediated and mitochondria-mediated pathways of apoptosis. Survivin has been also suggested to regulate cell division during mitosis. Indeed, survivin is the only one of IAPs that is tightly connected to the cell cycle being upregulated in the G2 /M phase. Inside the dividing cell, survivin is found incorporated in centrosomes and mitotic spindles, and relocates to midbodies in the late telophase. Disruption of survivin function by negative mutation or by introduction of anti-sense oligonucleotides results in a cell-division defect. Survivin is abundantly expressed in all the most common human cancers and in transformed cell lines, while most normal differentiated adult tissues do not express this molecule. A few adult tissues reported to express survivin include the spleen, the testes, the thymi, the placentas, and the colonic crypts.
In the present study we demonstrate high levels of the anti-apoptotic protein survivin extracellularly in plasma and synovial fluid of patients with RA. In all the cases but one, high levels of survivin were associated with the erosive type of joint disease. Moreover, it is demonstrated that autoantibody responses to survivin led to a more benign (non-erosive) course of RA. The latter finding may have potential therapeutic consequences.
