Implication of the toll-like receptor 4 pathway in the response to interferon-β in multiple sclerosis
Article first published online: 25 OCT 2011
Copyright © 2011 American Neurological Association
Annals of Neurology
Volume 70, Issue 4, pages 634–645, October 2011
How to Cite
Bustamante, M. F., Fissolo, N., Río, J., Espejo, C., Costa, C., Mansilla, M. J., Lizasoain, I., Angeles Moro, M., Carmen Edo, M., Montalban, X. and Comabella, M. (2011), Implication of the toll-like receptor 4 pathway in the response to interferon-β in multiple sclerosis. Ann Neurol., 70: 634–645. doi: 10.1002/ana.22511
- Issue published online: 25 OCT 2011
- Article first published online: 25 OCT 2011
- Accepted manuscript online: 7 JUN 2011 01:19PM EST
- Manuscript Accepted: 31 MAY 2011
- Manuscript Revised: 3 MAY 2011
- Manuscript Received: 17 FEB 2011
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.
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.
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.
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