Regulation of Immunomodulatory Cytokine Secretion by IFNb-1a is Mediated through Up-regulation of IRF7-SOCS1 Signaling in Monocytes from Patients with Relapsing-Remitting Multiple Sclerosis

Abstract

Abstract Objective To explore the mechanism by which IFNb-1a modulates cytokine production in monocytes from patients with relapsing-remitting multiple sclerosis (RRMS). Methods 91 RRMS patients and 77 control subjects were enrolled in the study. Magnetic resonance imaging (MRI) scans were used to detect the brain T2 and T1 lesion volume. Serum, cerebrospinal fluid (CSF) and peripheral blood CD14+ monocytes were collected for flow cytometry, RT-PCR, Western blotting and ELISA. Results As compared to the control subjects, IL-23 was increased in serum and CSF, while IL-27 was decreased in CSF of the RRMS patients. Serum IL-23 levels were positively correlated with brain MRI T2 and T1 lesion volumes in RRMS patients. CD14+ monocytes from RRMS patients showed decreased percentage of IL-27, IL-10 and IL-4, and increased percentage of IL-23; secreted lower levels of IL-27, IL-12p70 and IL-4, and higher levels of IL-23; and exhibited decreased gene expression of IFNb-1, IFNAR1, IFNAR2, SOCS1, TLR7 and MyD88. IFNb-1a in vitro treatment of monocytes from RRMS patients induced IL-27 and inhibited IL-23 production, increased gene expression of IRF7, MyD88 and SOCS1, and induced protein expression of IFNAR1, pSTAT1, IRF7, and SOCS1. STAT1 inhibitor diminished IFNb-1a-mediated STAT1 phosphorylation and up-regulation of IRF7 and SOCS1, while siRNA IRF7 abolished the IFNb-1a-mediated induction of SOCS1 in monocytes. Both STAT1 inhibitor and siRNA IRF7 impaired IFNb-1a-mediated regulation of IL-27 and IL-23. Conclusion Our study demonstrated that IRF7 is critical for the IFNb-mediated upregulation of SOCS1, which mediates IFNb-1a-induced up-regulation of IL-27 and down-regulation of IL-23 cytokine production in monocytes from RRMS patients.