Systemic IFN-β treatment induces apoptosis of peripheral immune cells in MS patients
Institute of Neuroimmunology, Neuroscience Research Center, Humboldt-University, NWFZ 2680, Charité, 10098 Berlin, Germany. Journal of Neuroimmunology
(Impact Factor: 2.47).
05/2003; 137(1-2):187-96. DOI: 10.1016/S0165-5728(03)00074-2
In multiple sclerosis (MS), an impaired apoptotic deletion of activated CNS-specific immune cells, leading to their pathogenic persistence, has been suggested to maintain chronic brain inflammation. We here investigated whether interferon-beta (IFN-beta) therapy induces apoptosis of peripheral immune cells. Serial blood samples from 127 relapsing-remitting MS patients were analyzed prior to the initiation of a weekly IFN-beta 1a therapy and 4, 26, and 52 weeks thereafter. Peripheral immune cells were investigated for apoptosis and for the expression of apoptosis-regulatory genes CD95, CD95 ligand, FLIP, Bcl-2, Bcl-X(L), Bag-1, and caspase 3 by quantitative real-time PCR. Biological efficacy of IFN-beta treatment was checked by quantification of Mx expression (ELISA and real-time PCR). We found a significant increase in the apoptosis rate of immune cells in response to IFN-beta treatment, compared to baseline levels. While Bcl-2 levels were permanently and Bag-1 levels transiently elevated upon therapy, other apoptosis-regulatory genes revealed no alterations. Upregulation of Mx expression confirmed the activity of IFN-beta in vivo. These findings indicate that immunomodulatory IFN-beta therapy involves the induction of apoptotic cell death with the observed RNA upregulation of Bcl-2 family members rather reflecting a possible compensatory mechanism. The increased apoptosis susceptibility of peripheral immune cells may contribute to the known reduction of brain inflammatory lesions during IFN-beta treatment.
Available from: Bruno Gran
- "We did not find an increased rate of NK apoptosis in IFN-β treated MS patients. IFN-β induced apoptosis of unfractionated peripheral blood lymphocytes (PBLs) in MS patients (Gniadek et al., 2003). However IFN-β treated MS patients showed reduction and normalisation of ex vivo T cell apoptosis (Garcia- Merino et al., 2009). "
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ABSTRACT: Interferon-β (IFN-β) is known to expand regulatory CD56(bright) natural killer (NK) cells in multiple sclerosis (MS). In this cross-sectional study we show that MS patients treated with IFN-β alone or in combination with low-dose prednisolone displayed increased proportion of all NK cell subsets in the active phase of the cell cycle (Ki-67+). There was no difference in NK cell apoptosis markers. In vitro experiments showed that both IFN-β and IFN-β in combination with corticosteroids increased the proportion of Ki-67(+) NK cells. This study, although limited, shows that treatment with IFN-β affects NK cell cycle without altering NK cell apoptosis in MS patients.
Available from: Sergio E Baranzini
- "Caspase2 and Caspase10 belong to the a family of proteins that are act as anti-or pro-apoptotic regulators and are involved in a wide variety of cellular activities. Previous gene expression studies have involved IFNβ in the regulation of apoptosis in MS  . MAP3k1, occupies a pivotal rule in a network of phosphorylating enzymes integrating cellular response to a number of mitogenic and metabolic stimuli . "
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ABSTRACT: Transcription profiling studies reveal important insights in regards to molecular events that manifest in phenotypic outcomes such as response to drug therapy. Construction of computational models that accurately predict therapy response is only possible when precise data measurements, robust feature/gene selection, and advanced computational modeling methods are combined with stringent statistical validation and large scale verification of results. Due to the large number of gene expression measurements in transcriptional profiling studies, feature selection represents a bottleneck when constructing computational models. The degree of compromise between selection of the optimal feature set and computational efficiency results in many choices for candidate gene sets which leads to a wide range of classification accuracies. Furthermore, constructing a classification model using a larger-than-necessary gene set along with small number of samples may cause over-fitting the data, resulting in highly optimistic classification accuracies. In this study we present OSeMA, a fast, robust and accurate gene selection-classification framework which results in construction of classification models that are highly predictive of the rIFNB therapy response in multiple sclerosis patients. We assess the performance of OSeMA on held out test data. Additionally, we extensively evaluate OSeMA by comparing it to an exhaustive combinatorial gene selection-classification approach.
Available from: Terry L Moore
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ABSTRACT: Rheumatoid arthritis (RA) is characterized by increased synovial lining cellularity, inflammation, and destruction of cartilage and bone. During the pathogenesis of RA, synovial fibroblasts reenter the cell cycle and multiply in number. RA synovial fibroblasts express high levels of the MAP kinase p38, which may contribute to the production of interleukin-6 (IL-6) and matrix metalloproteinases (MMPs). IL-6 and MMP-1 promote inflammation and joint destruction, respectively. Taken together, these findings indicate that in RA the enhanced cell cycle activity and production of IL-6 and MMP-1 may be linked. Therefore, we sought to determine if the tumor suppressor gene product retinoblastoma (Rb), a negative regulator of cell cycle activity, inhibits IL-6, MMP-1, and p38 in RA synovial fibroblasts.
RA and non-RA synovial fibroblasts were examined by enzyme-linked immunosorbent assay (ELISA) for the relative expression of inactive hyperphosphorylated Rb (inactive Rb/total Rb). Ectopic Rb expression was mediated by infection with a replication-defective adenovirus that expresses Rb (Ad-Rb). A control replication-defective adenovirus that expresses beta-galactosidase (Ad-beta-gal) was used. Cell cycle activity was determined by flow cytometry. IL-6 and MMP-1 expression was examined by real-time polymerase chain reaction and ELISA. Expression and activation of p38 were determined by kinase assays and ELISA. The activity of p38 was enhanced by infecting RA synovial fibroblasts with a replication-defective adenovirus that expresses a constitutively active form of MAPK kinase 3 (Ad-CA-MKK3), an upstream activator of p38.
Quiescent RA, compared with non-RA synovial fibroblasts, displayed a 200% (P < 0.02) increase in the inactive Rb isoform. Proliferating RA synovial fibroblasts exhibited a 60% (P < 0.12) increase in the inactive Rb isoform compared with non-RA synovial fibroblasts. Increased levels of the active Rb isoform inhibited cell cycle progression and suppressed IL-6 and MMP-1 secretion in RA synovial fibroblasts, although the steady-state levels of IL-6 and MMP-1 messenger RNA remained unchanged. However, Rb overexpression had no effect on spontaneous or IL-1beta-induced production of IL-6 or MMP-1 in non-RA synovial fibroblasts. Ectopic Rb expression reduced the activity of p38. Ad-CA-MKK3 infection in RA synovial fibroblasts increased p38 phosphorylation, and MMP-1 but not IL-6 secretion. In contrast, Rb overexpression inhibited Ad-CA-MKK3-mediated phosphorylation of p38 and subsequent increase in MMP-1.
Rb-mediated suppression of IL-6 and MMP-1 occurs at a posttranscriptional level. However, Ad-Rb reduction of MMP-1 but not IL-6 requires inhibition of the p38 pathway. These results suggest that Rb negatively regulates p38 activation, leading to decreased MMP-1 secretion in RA synovial fibroblasts.
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