CD40-Mediated NF-κB Activation in B Cells Is Increased in Multiple Sclerosis and Modulated by Therapeutics

Chen, Ding; Ireland, Sara; Remington, Gina; Alvarez, Enríque; Racke, Michael K.; Greenberg, Benjamin; Frohman, Elliot M.; Monson, Nancy

doi:10.4049/jimmunol.1600782

Cited by 41 publications

(31 citation statements)

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“…It was previously shown that okadaic acid, an inhibitor of PP1 and PP2A, provoked NF-B phosphorylation in MG63 human osteosarcoma cells, but the specific contribution of PP1␣ was not explored (30). In our study, costimulation-related NF-B activity was determined by measuring the phosphorylation (Ser529) of the p65 subunit and its translocation to the nucleus by imaging flow cytometry (31)(32)(33). While costimulation induced the phosphorylation of NF-B (p65) in control siRNA-treated cells, this phosphorylation was completely inhibited in the PP1 KD cells ( Fig.…”

Section: Figmentioning

confidence: 86%

Protein Phosphatase 1α and Cofilin Regulate Nuclear Translocation of NF-κB and Promote Expression of the Anti-Inflammatory Cytokine Interleukin-10 by T Cells

Wabnitz

Kirchgessner

Jahraus

et al. 2018

Molecular and Cellular Biology

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While several protein serine/threonine kinases control cytokine production by T cells, the roles of serine/threonine phosphatases are largely unexplored. Here, we analyzed the involvement of protein phosphatase 1α (PP1α) in cytokine synthesis following costimulation of primary human T cells. Small interfering RNA (siRNA)-mediated knockdown of PP1α (PP1) or expression of a dominant negative PP1α (D95N-PP1) drastically diminished interleukin-10 (IL-10) production. Focusing on a key transcriptional activator of human IL-10, we demonstrate that nuclear translocation of NF-κB was significantly inhibited in PP1 or D95N-PP1 cells. Interestingly, knockdown of cofilin, a known substrate of PP1 containing a nuclear localization signal, also prevented nuclear accumulation of NF-κB. Expression of a constitutively active nonphosphorylatable S3A-cofilin in D95N-PP1 cells restored nuclear translocation of NF-κB and IL-10 expression. Subpopulation analysis revealed that defective nuclear translocation of NF-κB was most prominent in CD4 CD45RA CXCR3 T cells that included IL-10-producing T2 cells. Together these findings reveal novel functions for PP1α and its substrate cofilin in T cells namely the regulation of the nuclear translocation of NF-κB and promotion of IL-10 production. These data suggest that stimulation of PP1α could limit the overwhelming immune responses seen in chronic inflammatory diseases.

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Section: Figmentioning

confidence: 86%

Protein Phosphatase 1α and Cofilin Regulate Nuclear Translocation of NF-κB and Promote Expression of the Anti-Inflammatory Cytokine Interleukin-10 by T Cells

Wabnitz

Kirchgessner

Jahraus

et al. 2018

Molecular and Cellular Biology

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“…In line with the differences found here, aberrant STAT phosphorylation signaling in peripheral blood mononuclear cells from MS patients has been reported (28) . The NFkβ pathway has been reported to be overactivated in PBMCs from patients with MS (29,30) as well as to contribute to the genetic susceptibility of the disease (31,32) . Our analysis supports the systemic pro-inflammatory state of PBMCs in MS.…”

Section: Discussionmentioning

confidence: 99%

Prediction of combination therapies based on topological modeling of the immune signaling network in Multiple Sclerosis

Bernardo-Faura

Rinas

Wirbel

et al. 2019

Preprint

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One sentence summary:A new approach to predict combination therapies based on modeling signaling networks using phosphoproteomics from Multiple Sclerosis patients identifies deregulated pathways and new drug combinations. Significance statementMultiple Sclerosis (MS) is a major health problem, leading to significant disability and patient suffering. Although chronic activation of the immune system is a hallmark of the disease, its pathogenesis is poorly understood. Further, current treatments only ameliorate the disease and may produce severe side effects.Here, we applied a network-based modeling approach based on phosphoproteomic data upon perturbation with ligands and drugs of healthy donors and MS patients to create donor-specific models. The models uncover the differential activation in signaling wiring between healthy donors, untreated patients and those under different treatments.Further, based in the patient-specific networks, a new approach identifies drug combinations to revert signaling to a healthy-like state.

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“…It has a wide range of symptoms including mental, physical, and psychological problems according to the recent Atlas of MS (2013) published by the MS International Federation. The global median prevalence of MS has increased from 30 to 33 cases per 100,000 people from 2008 to 2013 respectively [2,4]. Significantly, the prevalence rate of MS in Jordan increased to 39 per 100,000 people in the period from 2004 to 2005 [5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

“…One of the most non-human leukocyte antigen (non-HLA) loci is found within the cluster of differentiation 40 (CD40) gene [11]. Recent studies support the pathogenic role of CD40 in a number of autoimmune diseases including MS [4]. CD40 belongs to the tumor necrosis factor (TNF) receptor superfamily and is expressed mainly on B cells, microglia, macrophages, and other antigen-presenting cells (APCs) [9,11].…”

Section: Introductionmentioning

confidence: 99%

“…CD40 belongs to the tumor necrosis factor (TNF) receptor superfamily and is expressed mainly on B cells, microglia, macrophages, and other antigen-presenting cells (APCs) [9,11]. CD40 plays an essential role in the development of normal B cell responses and, therefore, immune regulation and homeostasis [4,11]. Another gene of the non-major histocompatibility complex (MHC) MS genes was recognized as the interleukin 7 receptor gene (IL7R), which is translated to a functional cell receptor for Interleukin 7 (IL-7) [12,13].…”

Section: Introductionmentioning

confidence: 99%

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Association of Multiple Sclerosis Phenotypes with Single Nucleotide Polymorphisms of IL7R, LAG3, and CD40 Genes in a Jordanian Population: A Genotype-Phenotype Study

2020

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It is thought that genetic variations play a vital role in the Multiple Sclerosis (MS) etiology. However, the role of genetic factors that influence the clinical features of MS remains unclear. We investigated the correlation between 21 single nucleotide polymorphisms within three genes (IL7R, LAG3, and CD40) and MS clinical characteristics in the Jordanian population. Blood samples and clinical phenotypic data were collected from 218 Arab Jordanian MS patients, vitamin D was measured, genomic DNA was extracted, and genotyping of the candidate genes’ polymorphisms were analyzed using the Sequenom MassARRAY® system. The association of these single nucleotide polymorphisms (SNPs) with MS was performed using a Chi-square, Fisher exact test, and one-way ANOVA. We found a significant association between vitamin D deficiency and three SNPs of the IL7R gene, namely rs987107 (P-value = 0.047), rs3194051 (P-value = 0.03), and rs1494571 (P-value = 0.036), in addition to two SNPs of CD40, namely rs1883832 and rs6074022 (P-value = 0.049 for both). rs3194051 of the IL7R gene (P-value = 0.003) and rs1922452 of the LAG3 gene (P-value = 0.028) were strongly associated with comorbidity. The number of relapses before drug onset was found to be correlated with IL7R SNPs rs969128 (P-value = 0.04) and rs1494555 (P-value = 0.027), whereas the expanded disability status scale (EDSS) was associated with rs1494555 polymorphism of IL7R gene (P-value = 0.026). Current findings indicate important correlations between certain SNPs and the risk of various phenotypes of multiple sclerosis in the Jordanian community. Therefore, this will not only contribute to the understanding of MS, but will also assist with the development of personalized treatment procedures.

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CD40-Mediated NF-κB Activation in B Cells Is Increased in Multiple Sclerosis and Modulated by Therapeutics

Cited by 41 publications

References 42 publications

Protein Phosphatase 1α and Cofilin Regulate Nuclear Translocation of NF-κB and Promote Expression of the Anti-Inflammatory Cytokine Interleukin-10 by T Cells

Protein Phosphatase 1α and Cofilin Regulate Nuclear Translocation of NF-κB and Promote Expression of the Anti-Inflammatory Cytokine Interleukin-10 by T Cells

Prediction of combination therapies based on topological modeling of the immune signaling network in Multiple Sclerosis

Association of Multiple Sclerosis Phenotypes with Single Nucleotide Polymorphisms of IL7R, LAG3, and CD40 Genes in a Jordanian Population: A Genotype-Phenotype Study

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