Interferon- beta modulates STAT6-activated inflammatory gene expression through the induction of SHP-1 in multiple sclerosis PBMCs

• Published in: Multiple sclerosis 2008-09, Vol.14, p.S232-S232
• Main Authors: Massa, P T, Christophi, G P, Mihai, C, Mejico, L L, Jubelt, B
• Format: Article
• Language: English
• ISSN: 1352-4585

Background: The protein tyrosine phosphatase SHP-1 is a crucial negative regulator of proinflammatory cytokine signaling both in the immune and central nervous systems (CNS). Mice lacking SHP-1 display pronounced virus-induced inflammatory demyelinating disease in the CNS. We have recently reported that SHP-1 activity is induced by interferon- beta (IFN- beta ) both in the CNS and immune system of mice (Christophi et al., J Neurochem. 2008). Also, we have shown that peripheral blood mononuclear cells (PBMCs) of multiple sclerosis (MS) patients display a stable deficiency of SHP-1 expression that leads to heightened STAT6 phosphorylation (pSTAT6) and increased STAT6-activated gene expression relevant to the mechanisms of inflammatory demyelination (Christophi et al., Lab Invest. 2008). Objective: To examine whether SHP-1 expression and activity is modulated by IFN- beta . Methods: Cultured PBMCs of normal subjects and MS patients were treated with IFN- beta , and SHP-1 expression, pSTAT6 and pSTAT1 activation, and inflammatory gene expression were analyzed. Results: Treatment of cultured PBMCs from MS patients with IFN- beta increased the expression of SHP-1 to levels seen in PBMCs of normal control subjects. Moreover, IFN- beta treatment significantly lowered levels of pSTAT6 in PBMCs of MS patients, consistent with heightened SHP-1 activity. Conversely, depleting SHP-1 using siRNA effectively increased the levels of pSTAT6 in PBMCs of normal subjects to levels equal to MS patients and abolished the suppression of pSTAT6 by IFN-b. Finally, multiple STAT6-responsive genes were increased in MS PBMCs relative to PBMCs of normal subjects and these levels were reduced to normal values with IFN- beta . To the contrary, STAT1 phosphorylation and STAT1-responsive genes were increased following IFN- beta treatment Conclusions: Thus, cultured PBMCs of MS patients display a stable deficiency of SHP-1 expression, which affects SHP-1 activity on STAT6 and the ability to regulate STAT6-responsive genes that may be relevant to MS inflammatory disease processes.