Home LiteratureArticle Details
PMID: 22711062 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't

Interferon-beta-1b-induced short- and long-term signatures of treatment activity in multiple sclerosis.

The pharmacogenomics journal ·Vol. 13 ·No. 5 ·2013-10-00 ·Pages 443-51

Croze E, Yamaguchi KD, Knappertz V, Reder AT, Salamon H

Abstract

Interferon beta (IFNβ) reduces disease burden in relapsing-remitting multiple sclerosis (MS) patients. In this study, IFNβ-1b-treated MS patient gene expression profiles and biological knowledgebases were integrated to study IFNβ's pleiotropic mechanisms of action. Genes involved in immune regulation, mitochondrial fatty acid metabolism and antioxidant activity were discovered. Plausible mediators of neuronal preservation included NRF2, downregulation of OLA1, an antioxidant suppressor, and the antioxidant gene ND6, implicated in optic neuropathy and MS-like lesions. Network analysis highlighted IKBKE, which likely has a role in both viral response and energy metabolism. A comparative analysis of therapy-naive MS- and IFNβ-associated gene expression suggests an IFNβ insufficiency in MS. We observed more gene expression changes in long-term treatment than during acute dosing. These distinct short- and long-term effects were driven by different transcription factors. Multi-gene biomarker signatures of IFNβ treatment effects were developed and subsequently confirmed in independent IFNβ-1b-treated MS studies, but not in glatiramer acetate-treated patients.

MeSH Terms
Adenosine Triphosphatases/genetics,immunology,metabolism Adjuvants, Immunologic/therapeutic use Adult Antioxidants/metabolism Biomarkers, Pharmacological/metabolism Down-Regulation Fatty Acids/genetics,immunology,metabolism Female GTP-Binding Proteins/genetics,immunology,metabolism Humans I-kappa B Kinase/genetics,immunology,metabolism Interferon beta-1b Interferon-beta/immunology,therapeutic use Male Middle Aged Mitochondria/genetics,immunology,metabolism Multiple Sclerosis/drug therapy,genetics,immunology NADH Dehydrogenase/genetics,immunology,metabolism NF-E2-Related Factor 2/genetics,immunology,metabolism Transcription Factors/genetics,immunology,metabolism Transcriptome
Chemicals
Adjuvants, Immunologic Antioxidants Biomarkers, Pharmacological Fatty Acids NF-E2-Related Factor 2 NFE2L2 protein, human Transcription Factors Interferon beta-1b Interferon-beta MT-ND6 protein, human NADH Dehydrogenase I-kappa B Kinase IKBKE protein, human Adenosine Triphosphatases GTP-Binding Proteins OLA1 protein, human
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Croze E
1] Global Medical Affairs, Bayer HealthCare Pharmaceuticals, San Francisco, CA, USA [2] International Review of Investigational Science, Lafayette, CA, USA.
Yamaguchi K D
Knappertz V
Reder A T
Salamon H
References (51)
51 references, click to expand
  1. OLA1, an Obg-like ATPase, suppresses antioxidant response via nontranscriptional mechanisms.
    Proc Natl Acad Sci U S A. 2009 Sep 8;106(36):15356-61 PMID: 19706404
  2. Reduced glucose metabolism in the frontal cortex and basal ganglia of multiple sclerosis patients with fatigue: a 18F-fluorodeoxyglucose positron emission tomography study.
    Neurology. 1997 Jun;48(6):1566-71 PMID: 9191767
  3. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway.
    Brain. 2011 Mar;134(Pt 3):678-92 PMID: 21354971
  4. Confirmation of the 14568 mutation in the mitochondrial ND6 gene as causative in Leber's hereditary optic neuropathy.
    Ophthalmic Genet. 2002 Sep;23(3):191-7 PMID: 12324878
  5. Innovations driving biomarker evaluation and use.
    Biomark Med. 2010 Dec;4(6):779-81 PMID: 21133694
  6. Molecular mechanisms of Nrf2-mediated antioxidant response.
    Mol Carcinog. 2009 Feb;48(2):91-104 PMID: 18618599
  7. IFN-beta pharmacogenomics in multiple sclerosis.
    Pharmacogenomics. 2010 Aug;11(8):1137-48 PMID: 20712530
  8. The challenge of multiple sclerosis: how do we cure a chronic heterogeneous disease?
    Ann Neurol. 2009 Mar;65(3):239-48 PMID: 19334069
  9. How cells respond to interferons.
    Annu Rev Biochem. 1998;67:227-64 PMID: 9759489
  10. A type I interferon signature in monocytes is associated with poor response to interferon-beta in multiple sclerosis.
    Brain. 2009 Dec;132(Pt 12):3353-65 PMID: 19741051
  11. Interferon-beta mechanisms of action in multiple sclerosis.
    Neurology. 2010 Jan 5;74 Suppl 1:S17-24 PMID: 20038758
  12. Immunopathogenesis of multiple sclerosis.
    Int Rev Neurobiol. 2007;79:99-126 PMID: 17531839
  13. The Nrf2-ARE pathway: an indicator and modulator of oxidative stress in neurodegeneration.
    Ann N Y Acad Sci. 2008 Dec;1147:61-9 PMID: 19076431
  14. MxA: a biomarker for predicting multiple sclerosis disease activity.
    Neurology. 2010 Oct 5;75(14):1222-3 PMID: 20921508
  15. Free radicals-mediated damage in transmitochondrial cells harboring the T14487C mutation in the ND6 gene of mtDNA.
    FEBS Lett. 2005 Dec 19;579(30):6909-13 PMID: 16337195
  16. Cross-sectional study assessing long-term safety of interferon-beta-1b for relapsing-remitting MS.
    Neurology. 2010 Jun 8;74(23):1877-85 PMID: 20530324
  17. Neurodegeneration in multiple sclerosis: the role of oxidative stress and excitotoxicity.
    J Neurol Sci. 2008 Nov 15;274(1-2):48-53 PMID: 18684473
  18. Summaries of Affymetrix GeneChip probe level data.
    Nucleic Acids Res. 2003 Feb 15;31(4):e15 PMID: 12582260
  19. Interferon β-1b and glatiramer acetate effects on permanent black hole evolution.
    Neurology. 2011 Apr 5;76(14):1222-8 PMID: 21464426
  20. Differential gene expression and translational approaches to identify biomarkers of interferon beta activity in multiple sclerosis.
    J Interferon Cytokine Res. 2010 Oct;30(10):743-9 PMID: 20874251
  21. IFN-beta1b induces transient and variable gene expression in relapsing-remitting multiple sclerosis patients independent of neutralizing antibodies or changes in IFN receptor RNA expression.
    J Interferon Cytokine Res. 2008 May;28(5):317-31 PMID: 18547162
  22. Multiple sclerosis.
    Immunol Rev. 2005 Apr;204:208-31 PMID: 15790361
  23. Synergistic benefit in inflammatory arthritis by targeting I kappaB kinase epsilon and interferon beta.
    Ann Rheum Dis. 2009 Feb;68(2):257-63 PMID: 18653628
  24. Neuropathology of white matter disease in Leber's hereditary optic neuropathy.
    Brain. 2005 Jan;128(Pt 1):35-41 PMID: 15483043
  25. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS).
    Neurology. 1983 Nov;33(11):1444-52 PMID: 6685237
  26. IFN-beta-regulated genes show abnormal expression in therapy-naïve relapsing-remitting MS mononuclear cells: gene expression analysis employing all reported protein-protein interactions.
    J Neuroimmunol. 2008 Mar;195(1-2):116-20 PMID: 18279974
  27. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis.
    Ann Neurol. 2001 Jul;50(1):121-7 PMID: 11456302
  28. The natural history of multiple sclerosis: a geographically based study 10: relapses and long-term disability.
    Brain. 2010 Jul;133(Pt 7):1914-29 PMID: 20534650
  29. Multiple functions of the IKK-related kinase IKKepsilon in interferon-mediated antiviral immunity.
    Science. 2007 Mar 2;315(5816):1274-8 PMID: 17332413
  30. The protein kinase IKKepsilon regulates energy balance in obese mice.
    Cell. 2009 Sep 4;138(5):961-75 PMID: 19737522
  31. Pharmacogenomics of interferon-beta therapy in multiple sclerosis: baseline IFN signature determines pharmacological differences between patients.
    PLoS One. 2008 Apr 02;3(4):e1927 PMID: 18382694
  32. Effect of immunomodulation with human interferon-beta on early functional recovery from experimental spinal cord injury.
    Spine (Phila Pa 1976). 2007 Apr 15;32(8):873-80 PMID: 17426631
  33. Another detour on the Toll road to the interferon antiviral response.
    Nat Struct Mol Biol. 2004 Nov;11(11):1028-30 PMID: 15523474
  34. Low expression of interferon-stimulated genes in active multiple sclerosis is linked to subnormal phosphorylation of STAT1.
    J Neuroimmunol. 2002 Aug;129(1-2):205-15 PMID: 12161037
  35. Integration of genetic risk factors into a clinical algorithm for multiple sclerosis susceptibility: a weighted genetic risk score.
    Lancet Neurol. 2009 Dec;8(12):1111-9 PMID: 19879194
  36. Pathway Commons, a web resource for biological pathway data.
    Nucleic Acids Res. 2011 Jan;39(Database issue):D685-90 PMID: 21071392
  37. Efficacy of fumaric acid esters in the R6/2 and YAC128 models of Huntington's disease.
    PLoS One. 2011 Jan 31;6(1):e16172 PMID: 21297955
  38. The relationship between MRI and PET changes and cognitive disturbances in MS.
    J Neurol Sci. 2006 Jun 15;245(1-2):99-102 PMID: 16650436
  39. Pharmacogenomics of IFN-beta in multiple sclerosis: towards a personalized medicine approach.
    Pharmacogenomics. 2009 Jan;10(1):97-108 PMID: 19102719
  40. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.
    Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50 PMID: 16199517
  41. The type I interferon receptor: structure, function, and evolution of a family business.
    J Interferon Cytokine Res. 1999 Oct;19(10):1069-98 PMID: 10547147
  42. A global test for groups of genes: testing association with a clinical outcome.
    Bioinformatics. 2004 Jan 1;20(1):93-9 PMID: 14693814
  43. Is multiple sclerosis a mitochondrial disease?
    Biochim Biophys Acta. 2010 Jan;1802(1):66-79 PMID: 19607913
  44. Mechanisms of action of interferon-beta in multiple sclerosis.
    Springer Semin Immunopathol. 1996;18(1):125-48 PMID: 8984676
  45. Long-term genome-wide blood RNA expression profiles yield novel molecular response candidates for IFN-beta-1b treatment in relapsing remitting MS.
    Pharmacogenomics. 2010 Feb;11(2):147-61 PMID: 20136355
  46. Neutralizing antibodies to interferon beta-1b multiple sclerosis: a clinico-radiographic paradox in the BEYOND trial.
    Mult Scler. 2012 Feb;18(2):181-95 PMID: 21952094
  47. Molecular cloning and characterization of two novel retinoic acid-inducible orphan G-protein-coupled receptors (GPRC5B and GPRC5C).
    Genomics. 2000 Jul 1;67(1):8-18 PMID: 10945465
  48. Ketone body synthesis in the brain: possible neuroprotective effects.
    Prostaglandins Leukot Essent Fatty Acids. 2004 Mar;70(3):287-92 PMID: 14769487
  49. The current landscape and unmet needs in multiple sclerosis.
    Am J Manag Care. 2010 Sep;16(8 Suppl):S211-8 PMID: 20873945
  50. Glatiramer acetate: a review of its use in relapsing-remitting multiple sclerosis and in delaying the onset of clinically definite multiple sclerosis.
    Drugs. 2010 Aug 20;70(12):1545-77 PMID: 20687620
  51. IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci.
    Genes Immun. 2010 Jul;11(5):397-405 PMID: 20555355
Article Info
Journal
The pharmacogenomics journal
Abbr.
Pharmacogenomics J
ISSN
1473-1150
DOI
10.1038/tpj.2012.27
Published
2013-10-00
Epub
2012-00-19
Pages
443-51
Language
English
Region
United States
NLM ID
101083949
PMCID
PMC3793239
Subset
IM
External Links
PubMed source DOI: 10.1038/tpj.2012.27 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2