Inhibition of interferon-beta responses in multiple sclerosis immune cells associated with high-dose statins

Xuan Feng, Diana Han, Bharat K. Kilaru, Beverly S. Franek, Timothy B. Niewold, Anthony T. Reder

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Objective: To determine whether statins affect type 1 interferon responses in relapsing-remitting multiple sclerosis (RRMS). Design : Study effects of atorvastatin on type 1 interferon responses in Jurkat cells, mononuclear cells (MNCs) from therapy-naive patients with RRMS in vitro , and MNCs from interferon-treated RRMS patients in vivo in 4 conditions: no drug, statin only, interferon-beta only, and statin added on to interferon-beta therapy. Patients: The study examined clinically stable patients with RRMS: 21 therapy-naive patients and 14 patients receiving interferon-beta with a statin. Interventions: Statin effects on in vitro and in vivo interferon-beta-induced STAT1 transcription factor activation, expression of interferon-stimulated proteins in MNCs, and serum type 1 interferon activity. Results: In vitro, atorvastatin dose dependently inhibited expression of interferon-stimulated P-Y-STAT1 by 44% (P < .001), interferon regulatory factor 1 protein by 30% (P = .006), and myxovirus resistance 1 protein by 32% (P = .004) compared with no-statin control in MNCs from therapy-naive RRMS patients. In vivo, 9 of 10 patients who received high-dose statins (80 mg) had a significant reduction in interferon-beta therapy-induced serum interferon-α/β activity, whereas only 2 of 4 patients who received medium-dose statins (40 mg) had reductions. High-dose add-on statin therapy significantly blocked interferon-beta function, with less P-Y-STAT1 transcription factor activation, and reduced myxovirus resistance 1 protein and viperin protein production. Medium doses of statins did not change STAT1 activation. Conclusions: High-dose add-on statin therapy significantly reduces interferon-beta function and type 1 interferon responses in RRMS patients. These data provide a putative mechanism for how statins could counteract the beneficial effects of interferon-beta and worsen disease.

Original languageEnglish (US)
Pages (from-to)1303-1309
Number of pages7
JournalArchives of Neurology
Volume69
Issue number10
DOIs
StatePublished - Oct 2012
Externally publishedYes

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Hydroxymethylglutaryl-CoA Reductase Inhibitors
Interferon-beta
Multiple Sclerosis
Relapsing-Remitting Multiple Sclerosis
Interferon Type I
Interferons
Myxovirus Resistance Proteins
STAT1 Transcription Factor
Cell- and Tissue-Based Therapy
Transcriptional Activation
Cells
Dose
Interferon Regulatory Factor-1
Therapeutics
Therapy
Proteins
Jurkat Cells
Serum
Protein

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Cite this

Inhibition of interferon-beta responses in multiple sclerosis immune cells associated with high-dose statins. / Feng, Xuan; Han, Diana; Kilaru, Bharat K.; Franek, Beverly S.; Niewold, Timothy B.; Reder, Anthony T.

In: Archives of Neurology, Vol. 69, No. 10, 10.2012, p. 1303-1309.

Research output: Contribution to journalArticle

Feng, Xuan ; Han, Diana ; Kilaru, Bharat K. ; Franek, Beverly S. ; Niewold, Timothy B. ; Reder, Anthony T. / Inhibition of interferon-beta responses in multiple sclerosis immune cells associated with high-dose statins. In: Archives of Neurology. 2012 ; Vol. 69, No. 10. pp. 1303-1309.
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abstract = "Objective: To determine whether statins affect type 1 interferon responses in relapsing-remitting multiple sclerosis (RRMS). Design : Study effects of atorvastatin on type 1 interferon responses in Jurkat cells, mononuclear cells (MNCs) from therapy-naive patients with RRMS in vitro , and MNCs from interferon-treated RRMS patients in vivo in 4 conditions: no drug, statin only, interferon-beta only, and statin added on to interferon-beta therapy. Patients: The study examined clinically stable patients with RRMS: 21 therapy-naive patients and 14 patients receiving interferon-beta with a statin. Interventions: Statin effects on in vitro and in vivo interferon-beta-induced STAT1 transcription factor activation, expression of interferon-stimulated proteins in MNCs, and serum type 1 interferon activity. Results: In vitro, atorvastatin dose dependently inhibited expression of interferon-stimulated P-Y-STAT1 by 44{\%} (P < .001), interferon regulatory factor 1 protein by 30{\%} (P = .006), and myxovirus resistance 1 protein by 32{\%} (P = .004) compared with no-statin control in MNCs from therapy-naive RRMS patients. In vivo, 9 of 10 patients who received high-dose statins (80 mg) had a significant reduction in interferon-beta therapy-induced serum interferon-α/β activity, whereas only 2 of 4 patients who received medium-dose statins (40 mg) had reductions. High-dose add-on statin therapy significantly blocked interferon-beta function, with less P-Y-STAT1 transcription factor activation, and reduced myxovirus resistance 1 protein and viperin protein production. Medium doses of statins did not change STAT1 activation. Conclusions: High-dose add-on statin therapy significantly reduces interferon-beta function and type 1 interferon responses in RRMS patients. These data provide a putative mechanism for how statins could counteract the beneficial effects of interferon-beta and worsen disease.",
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AU - Han, Diana

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AU - Niewold, Timothy B.

AU - Reder, Anthony T.

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AB - Objective: To determine whether statins affect type 1 interferon responses in relapsing-remitting multiple sclerosis (RRMS). Design : Study effects of atorvastatin on type 1 interferon responses in Jurkat cells, mononuclear cells (MNCs) from therapy-naive patients with RRMS in vitro , and MNCs from interferon-treated RRMS patients in vivo in 4 conditions: no drug, statin only, interferon-beta only, and statin added on to interferon-beta therapy. Patients: The study examined clinically stable patients with RRMS: 21 therapy-naive patients and 14 patients receiving interferon-beta with a statin. Interventions: Statin effects on in vitro and in vivo interferon-beta-induced STAT1 transcription factor activation, expression of interferon-stimulated proteins in MNCs, and serum type 1 interferon activity. Results: In vitro, atorvastatin dose dependently inhibited expression of interferon-stimulated P-Y-STAT1 by 44% (P < .001), interferon regulatory factor 1 protein by 30% (P = .006), and myxovirus resistance 1 protein by 32% (P = .004) compared with no-statin control in MNCs from therapy-naive RRMS patients. In vivo, 9 of 10 patients who received high-dose statins (80 mg) had a significant reduction in interferon-beta therapy-induced serum interferon-α/β activity, whereas only 2 of 4 patients who received medium-dose statins (40 mg) had reductions. High-dose add-on statin therapy significantly blocked interferon-beta function, with less P-Y-STAT1 transcription factor activation, and reduced myxovirus resistance 1 protein and viperin protein production. Medium doses of statins did not change STAT1 activation. Conclusions: High-dose add-on statin therapy significantly reduces interferon-beta function and type 1 interferon responses in RRMS patients. These data provide a putative mechanism for how statins could counteract the beneficial effects of interferon-beta and worsen disease.

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