Interferon-β treatment in multiple sclerosis attenuates inflammatory gene expression through inducible activity of the phosphatase SHP-1

Abstract

Interferon-β is a current treatment for multiple sclerosis (MS). Interferon-β is thought to exert its therapeutic effects on MS by down-modulating the immune response by multiple potential pathways. Here, we document that treatment of MS patients with interferon β-1a (Rebif) results in a significant increase in the levels and function of the protein tyrosine phosphatase SHP-1 in PBMCs. SHP-1 is a crucial negative regulator of cytokine signaling, inflammatory gene expression, and CNS demyelination as evidenced in mice deficient in SHP-1. In order to examine the functional significance of SHP-1 induction in MS PBMCs, we analyzed the activity of proinflammatory signaling molecules STAT1, STAT6, and NF-κB, which are known SHP-1 targets. Interferon-β treatment in vivo resulted in decreased NF-κB and STAT6 activation and increased STAT1 activation. Further analysis in vitro showed that cultured PBMCs of MS patients and normal subjects had a significant SHP-1 induction following interferon-β treatment that correlated with decreased NF-κB and STAT6 activation. Most importantly, experimental depletion of SHP-1 in cultured PBMCs abolished the anti-inflammatory effects of interferon-β treatment, indicating that SHP-1 is a predominant mediator of interferon-β activity. In conclusion, interferon-β treatment upregulates SHP-1 expression resulting in decreased transcription factor activation and inflammatory gene expression important in MS pathogenesis.

Quantitative differences in the immunomodulatory effects of Rebif and Avonex in IFN-β 1a treated multiple sclerosis patients

“…Next, it was important to quantify the levels of several cytokine-inducible genes that where shown to be modulated in MS by interferon treatment (25, 38, 39). Several genes were quantified by real time RT-PCR in freshly isolated PBMC of normal subjects, RRMS patients and in three-month treated Rebif or Avonex RRMS patients (table II).…”

“…Amplification of each gene specific fragment was confirmed by examination of melting peaks, by agarose gel electrophoresis, and DNA sequencing. The primers used in the study were previously documented (12, 25). …”

“…IFN-β 1a treatment of patients with RRMS in vivo and also in vitro leukocyte cultures can reduce the activation of the transcription factors NF-κB and STAT6 and decrease downstream inflammatory gene expression regulated by those transcription factors (25). However, IFN-β 1a (Rebif) treatment signals directly to activate the transcription factor STAT1 and increase the expression genes containing STAT1 responsive sites in their promoter.…”

“…Additionally, IFN-β induces the activation of intracellular regulatory proteins. The inhibitory effects of IFN-β 1a treatment on cytokine signaling are at least partly mediated by the induced expression of the tyrosine phosphatase SHP-1 that acts as a broad negative regulator of STAT-1, STAT6, and NF-κB signaling and results in decreased inflammatory gene expression (25). …”

Oral Palmitoylethanolamide Treatment Is Associated with Reduced Cutaneous Adverse Effects of Interferon-β1a and Circulating Proinflammatory Cytokines in Relapsing–Remitting Multiple Sclerosis

“…Consistent with the reduced IL-17 serum levels in the um-PEA-treated group, we also found reduced TNF-α serum levels. Importantly, this effect is obtained under IFN-β1a treatment, which per se reduces the proinflammatory cytokine serum levels in MS [52][53][54]. Inflammatory mediators, such as IFN-γ and TNF-α are known key contributors to the induction and maintenance of autoimmune diseases [55][56][57][58].…”