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Published on: July 26, 2017
Implication of the Toll-like receptor 4 pathway in the response to interferon-β in multiple sclerosis
Marta F Bustamante1, Nicolás Fissolo, Jordi Río
1Centre d'Esclerosi Múltiple de Catalunya, CEM-Cat, Unitat de Neuroimmunologia Clínica, Hospital Universitari Vall d'Hebron (HUVH)-Universitat Autònoma de Barcelona, Passeig Vall d'Hebron 119-129, Barcelona, Spain.
Objective:
Interferon-beta (IFNβ) 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 IFNβ 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 IFNβ 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 IFNβ and elevated IFN receptor 1 (IFNAR1) expression in monocytes. Furthermore, the capacity of IFNβ 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 IFNβ 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 IFNβ.
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