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.
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 MSpatients. 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 MSpatients 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.
Authors: Sunny Malhotra; Jordi Río; Elena Urcelay; Ramil Nurtdinov; Marta F Bustamante; Oscar Fernández; Begoña Oliver; Uwe Zettl; David Brassat; Joep Killestein; Jeannette Lechner-Scott; Jelena Drulovic; Andrew Chan; Filippo Martinelli-Boneschi; Antonio García-Merino; Xavier Montalban; Manuel Comabella Journal: Brain Date: 2015-01-12 Impact factor: 13.501
Authors: Alexander Hundeshagen; Michael Hecker; Brigitte Katrin Paap; Charlotte Angerstein; Ole Kandulski; Christian Fatum; Christiane Hartmann; Dirk Koczan; Hans-Juergen Thiesen; Uwe Klaus Zettl Journal: J Neuroinflammation Date: 2012-06-22 Impact factor: 8.322
Authors: Michael Hecker; Brigitte Katrin Paap; Robert Hermann Goertsches; Ole Kandulski; Christian Fatum; Dirk Koczan; Hans-Peter Hartung; Hans-Juergen Thiesen; Uwe Klaus Zettl Journal: PLoS One Date: 2011-12-27 Impact factor: 3.240