Prolonged Interferon-Stimulated Gene and Protein Signatures in Multiple Sclerosis Induced by PEGylated IFN-ß-1a Compared to Non-PEGylated IFN-ß-1a.

Interferon (IFN)-ß-1a (Avonex) and longer half-life, polyethylene glycol-conjugated IFN-ß-1a (PEG-IFN-ß-1a, Plegridy), may generate different molecular responses. We identified different short-term and long-term in vivo global RNA signatures of IFN-stimulated genes in multiple sclerosis (MS) peripheral blood mononuclear cells and in selected paired serum immune proteins. At 6 h, non-PEGylated IFN-ß-1a injection upregulated expression of 136 genes and PEG-IFN-ß-1a upregulated 85. At 24 h, induction was maximal; IFN-ß-1a upregulated 476 genes and PEG-IFN-ß-1a now upregulated 598. Long-term PEG-IFN-ß-1a therapy increased expression of antiviral and immune-regulatory genes (IFIH1, TLR8, IRF5, TNFSF10 [TRAIL], STAT3, JAK2, IL15, and RB1) and IFN signaling pathways (IFNB1, IFNA2, IFNG, IRF7), but downregulated expression of inflammatory genes (TNF, IL1B, and SMAD7). Long-term PEG-IFN-ß-1a induced longer and stronger expression of Th1, Th2, Th17, chemokine, and antiviral proteins than long-term IFN-ß-1a. Long-term therapy also primed the immune system, evoking higher gene and protein induction after IFN reinjection at 7 months than at 1 month of PEG-IFN-ß-1a treatment. Both forms of IFN-ß balanced correlations of expression among these genes and proteins, with positive correlations between Th1 and Th2 families, quelling the "cytokine storm" of untreated MS. Both IFNs induced long-term, potentially beneficial, molecular effects on immune and possibly neuroprotective pathways in MS.