Expression and regulation of IFNalpha/beta receptor in IFNbeta-treated patients with multiple sclerosis.
BACKGROUND
The cytokine interferon beta (IFNbeta) is successfully used in the treatment of multiple sclerosis (MS), although there is a high degree of variability in the response. A common mechanism involved in the modulation of responsiveness to cytokines is represented by regulation of their receptor expression through autocrine ligand-mediated loops. The present study is aimed at investigating the regulation of IFNalpha/beta receptor (IFNAR) during IFNbeta therapy in patients with MS and at correlating it with the biologic responsiveness to the cytokine.


METHODS
Quantitative PCR measurements of IFNAR-1 and the three IFNAR-2 isoforms were performed in 141 patients after short-term and long-term treatment. Patients were also regularly screened for anti-IFNbeta neutralizing antibodies (NAbs). IFN-inducible myxovirus resistance protein A messenger RNA was used as an indicator of bioactivity.


RESULTS
Pretreatment levels of IFNAR-2 in patients were lower overall than in controls (p = 0.038), and high levels correlated with greater bioactivity. Upon prolonged treatment, NAb-negative patients displayed a state of decreased transmembrane IFNAR-2 expression (p < or = 0.025), whereas levels of soluble IFNAR-2 were slightly increased (p < 0.0001). The presence of NAbs reversed these effects (p < or = 0.0056). In NAb-positive patients, pretreatment expression levels of both transmembrane IFNAR-2 isoforms were significantly lower than in NAb-negative patients (p < or = 0.0089).


CONCLUSIONS
Findings show that interferon-alpha/beta receptor (IFNAR)-2 isoforms are important regulators of the responsiveness to endogenous and systemically administered interferon beta (IFNbeta). They show a dual action, agonistic and antagonistic, that influences both the magnitude and the nature of the biologic response to IFNbeta. Levels of IFNAR-2 are regulated with the aim of keeping the body in a state of equilibrium, even when nonphysiologic stimuli are present.
Gilli
F
F
Centro di Riferimento Regionale Sclerosi Multipla & Neurobiologia Clinica, ASO S. Luigi Gonzaga, Regione Gonzole, Orbassano, Torino, Italy. neurobiologia@sanluigi.piemonte.it
Valentino
P
P
Caldano
M
M
Granieri
L
L
Capobianco
M
M
Malucchi
S
S
Sala
A
A
Marnetto
F
F
Bertolotto
A
A
D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D002462:Cell Membrane / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D004351:Drug Resistance / Q000235:genetics* / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use; D016899:Interferon-beta / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology* / Q000503:physiopathology; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D017434:Protein Structure, Tertiary / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000187:drug effects* / Q000235:genetics* / Q000276:immunology; D012189:Retrospective Studies; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology
D007155:Immunologic Factors; D020033:Protein Isoforms; D012333:RNA, Messenger; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta