Implication of the Toll-Like Receptor 4 Pathway in the Response to Interferon-β in Multiple Sclerosis

Objective: Interferon-beta (IFN beta) has demonstrated beneficial effects reducing disease activity in multiple sclerosis (MS) patients, but a relatively large proportion of patients do not respond to treatment. Here we aimed to investigate the roles of the Toll-like receptor 4 (TLR4) and the type I IFN pathways in the response to IFN beta in MS patients. Methods: The expression levels of several components of the TLR4 and the type I IFN pathways were determined by flow cytometry and real-time polymerase chain reaction (PCR) in peripheral blood mononuclear cells (PBMCs) from a cohort of 85 MS patients treated for at least 2 years with IFN beta and classified into responders, intermediate responders, and nonresponders based on their clinical response to treatment. Thirty-two healthy controls were also included in the study for comparison purposes. Results: Compared to responders and controls, PBMCs from nonresponders and intermediate responders were characterized by increased baseline expression levels of endogenous IFN beta and elevated IFN receptor 1 (IFNAR1) expression in monocytes. Furthermore, the capacity of IFN beta to induce its own expression was deficient in cells from nonresponders compared with responders. Baseline expression of the interleukin-1 receptor-associated kinase 3 (IRAK3), a negative regulator of TLR4 signaling primarily expressed in monocytes, was found to be significantly decreased in IFN beta responders compared with nonresponders. Interpretation: These findings provide evidence of the involvement of the TLR4 and type I IFN signaling pathways in the response to IFN beta. ANN NEUROL 2011;70:634-645