Implication of the Toll-like receptor 4 pathway in the response to interferon-β in multiple sclerosis.
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.


CONCLUSIONS
These findings provide evidence of the involvement of the TLR4 and type I IFN signaling pathways in the response to IFNβ.
Centre 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.
Marta F
MF
Bustamante
Nicolás
N
Fissolo
Jordi
J
Río
Carmen
C
Espejo
Carme
C
Costa
María José
MJ
Mansilla
Ignacio
I
Lizasoain
María Angeles
MA
Moro
Mari
M
Carmen Edo
Xavier
X
Montalban
Manuel
M
Comabella
D000328:Adult; D015331:Cohort Studies; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D016896:Treatment Outcome
D007155:Immunologic Factors; D007370:Interferon Type I; D051197:Toll-Like Receptor 4; D016899:Interferon-beta