Biological markers of interferon-beta therapy: comparison among interferon-stimulated genes MxA, TRAIL and XAF-1.
Biological activity of interferon-beta (IFNbeta) can be assessed by measuring IFN-stimulated genes (ISGs). Among them, myxovirus resistance protein A (MxA) appears to have the highest specificity, but it has no role in the pathogenesis of multiple sclerosis (MS). To investigate the reliability of MxA as a biomarker, we compared its expression to that of two other ISGs: TNF-related apoptosis-inducing ligand (TRAIL) and X-linked inhibitor of apoptosis factor-1 (XAF-1). Both were shown to be involved in immunoregulatory mechanisms and might play a role in MS. Quantitative-PCR measurements were performed in peripheral blood mononuclear cells from 73 MS patients after short-term and long-term treatment with IFNbeta. A time-dependent response for multiple ISGs was observed in all patients after short-term treatment. In contrast, long-term treatment induced concurrent inhibition of ISGs in 12.3% (9/73) of patients, in whom neutralizing antibodies (NAbs) were detectable. Besides, 22% (16/73) of chronically treated patients showed a non-NAbs-related abrogation of TRAIL expression. In summary, 1) MxA expression was significantly higher than both TRAIL and XAF-1, and 2) MxA was the most sensitive gene to detect decreased bioavailability due to NAbs. These findings identify MxA as an appropriate biomarker for IFNbeta, although there is no evidence for a functional role of it in MS.
Gilli
F
F
Centro di Riferimento Regionale Sclerosi Multipla (CReSM) & Neurobiologia Clinica, ASO S. Luigi Gonzaga, Orbassano, Torino, Italy.
Marnetto
F
F
Caldano
M
M
Sala
A
A
Malucchi
S
S
Capobianco
M
M
Bertolotto
A
A
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D051017:Apoptosis Regulatory Proteins / Q000097:blood / Q000235:genetics*; D015415:Biomarkers / Q000097:blood; D005260:Female; D019204:GTP-Binding Proteins / Q000097:blood / Q000235:genetics*; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D000068576:Interferon beta-1b; D016899:Interferon-beta / Q000627:therapeutic use*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood / Q000235:genetics*; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D064547:Myxovirus Resistance Proteins; D009363:Neoplasm Proteins / Q000097:blood / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D012016:Reference Values; D053221:TNF-Related Apoptosis-Inducing Ligand; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D015415:Biomarkers; D047908:Intracellular Signaling Peptides and Proteins; C579071:MX1 protein, human; D008562:Membrane Glycoproteins; D064547:Myxovirus Resistance Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; C417551:XAF1 protein, human; D000068576:Interferon beta-1b; D016899:Interferon-beta; D019204:GTP-Binding Proteins