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The role of cell type-specific responses in IFN-? therapy of multiple sclerosis.

ABSTRACT: The mechanism of IFN-? therapy in relapsing-remitting multiple sclerosis (RRMS) is not well understood, but induction of apoptosis in specific leukocyte subsets is likely to be important. Enhanced expression of TNFSF10 or TNF-related apoptosis-inducing ligand (TRAIL) mRNA in unseparated leukocytes has been put forward as a therapeutic response marker, but it is unclear which leukocyte subsets express TRAIL. We investigated the basis of TRAIL expression in response to IFN-? by studying activation of STATs 1, 3, and 5, p38 MAPK, and NF-?B in different leukocyte subsets of patients with RRMS. Monocytes, B cells, and T cells showed substantial differences in the activation of p38 and the STATs in response to i.m. injection of IFN-?1a or stimulation in vitro. Induction of cell-surface TRAIL, analyzed in nine leukocyte subsets, was observed only on monocytes and granulocytes and correlated with the activation of p38 and/or NF-?B in these subsets only, in agreement with previous work in fibroblasts showing that the induction of TRAIL in response to IFN-? depends on the activation of p38 and NF-?B as well as STATs 1 and 2. We propose that, in myeloid cells, the differential activation of p38 and NF-?B and induction of TRAIL, which sensitizes cells to apoptosis, can help to explain differences in responsiveness to IFN-? therapy among patients with RRMS and, furthermore, that such differential patterns of activation and expression may also be important in understanding the therapeutic responses to IFN-?/? in hepatitis and cancer.

SUBMITTER: Zula JA

PROVIDER: S-EPMC3241780 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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The role of cell type-specific responses in IFN-β therapy of multiple sclerosis.

Zula Joana A JA Green Holly C HC Ransohoff Richard M RM Rudick Richard A RA Stark George R GR van Boxel-Dezaire Anette H H AH

Proceedings of the National Academy of Sciences of the United States of America 20111121 49

The mechanism of IFN-β therapy in relapsing-remitting multiple sclerosis (RRMS) is not well understood, but induction of apoptosis in specific leukocyte subsets is likely to be important. Enhanced expression of TNFSF10 or TNF-related apoptosis-inducing ligand (TRAIL) mRNA in unseparated leukocytes has been put forward as a therapeutic response marker, but it is unclear which leukocyte subsets express TRAIL. We investigated the basis of TRAIL expression in response to IFN-β by studying activation ...[more]

PMID: 22106296

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Project description:BACKGROUND:Multiple sclerosis (MS) is a heterogeneous disease. In order to understand the partial responsiveness to IFNbeta in Relapsing Remitting MS (RRMS) we studied the pharmacological effects of IFNbeta therapy. METHODOLOGY:Large scale gene expression profiling was performed on peripheral blood of 16 RRMS patients at baseline and one month after the start of IFNbeta therapy. Differential gene expression was analyzed by Significance Analysis of Microarrays. Subsequent expression analyses on specific genes were performed after three and six months of treatment. Peripheral blood mononuclear cells (PBMC) were isolated and stimulated in vitro with IFNbeta. Genes of interest were measured and validated by quantitative realtime PCR. An independent group of 30 RRMS patients was used for validation. PRINCIPAL FINDINGS:Pharmacogenomics revealed a marked variation in the pharmacological response to IFNbeta between patients. A total of 126 genes were upregulated in a subset of patients whereas in other patients these genes were downregulated or unchanged after one month of IFNbeta therapy. Most interestingly, we observed that the extent of the pharmacological response correlates negatively with the baseline expression of a specific set of 15 IFN response genes (R = -0.7208; p = 0.0016). The negative correlation was maintained after three (R = -0.7363; p = 0.0027) and six (R = -0.8154; p = 0.0004) months of treatment, as determined by gene expression levels of the most significant correlating gene. Similar results were obtained in an independent group of patients (n = 30; R = -0.4719; p = 0.0085). Moreover, the ex vivo results could be confirmed by in vitro stimulation of purified PBMCs at baseline with IFNbeta indicating that differential responsiveness to IFNbeta is an intrinsic feature of peripheral blood cells at baseline. CONCLUSION:These data imply that the expression levels of IFN response genes in the peripheral blood of MS patients prior to treatment could serve a role as biomarker for the differential clinical response to IFNbeta.

Dataset Information

The role of cell type-specific responses in IFN-? therapy of multiple sclerosis.

Publications

The role of cell type-specific responses in IFN-β therapy of multiple sclerosis.

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