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Implication of the toll‐like receptor 4 pathway in the response to interferon‐β in multiple sclerosis
Author(s) -
Bustamante Marta F.,
Fissolo Nicolás,
Río Jordi,
Espejo Carmen,
Costa Carme,
Mansilla María José,
Lizasoain Ignacio,
Angeles Moro María,
Carmen Edo Mari,
Montalban Xavier,
Comabella Manuel
Publication year - 2011
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.22511
Subject(s) - multiple sclerosis , interferon , tlr4 , immunology , peripheral blood mononuclear cell , toll like receptor , flow cytometry , receptor , medicine , signal transduction , interferon type i , biology , innate immune system , biochemistry , in vitro
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. ANN NEUROL 2011;70:634–645