TRAIL and TRAIL receptors splice variants during long-term interferon β treatment of patients with multiple sclerosis: evaluation as biomarkers for therapeutic response.
OBJECTIVE
We aimed to assess the effects of interferon β (IFNβ) treatment on the expression of the splice variants of the Tumour necrosis factor-Related Apoptosis Inducing Ligand (TRAIL) and its receptors in different cell subpopulations (CD14+, CD4+ and CD8+) from patients with multiple sclerosis (MS), and to determine whether this expression discriminated responders from non-responders to IFNβ therapy.


METHODS
We examined mRNA expression of the TRAIL and TRAIL receptors variants in patients with MS, at baseline and after one year of IFNβ therapy, according to responsiveness to this drug.


RESULTS
Long-term therapy with IFNβ increased the expression of TRAIL-α in T cell subsets exclusively from responders and decreased the expression of the isoform 2 of TRAILR-2 in monocytes from responders as well as non-responders. Lower expression of TRAIL-α, and higher expression of TRAIL-β in monocytes and T cells, was found before the onset of IFNβ therapy in patients who will subsequently become responders. Baseline expression of TRAILR-1 was also significantly higher in monocytes and CD4+ T cells from responders.


CONCLUSIONS
The present study shows that long-term IFNβ treatment has a direct influence on TRAIL-α and TRAILR-2 isoform 2 expression. Besides, receiver operating characteristic analysis revealed that the baseline expression of TRAIL-α in monocytes and T cells, and that of TRAILR-1 in monocytes and CD4+ T cells, showed a predictive value of the clinical response to IFNβ therapy, pointing to a role of TRAIL system in the mechanism of action of IFNβ in MS that will need further investigation.
Research Laboratory, UGCI Neurociencias Clínicas, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga/Universidad de Málaga, Málaga, Spain.
Carlos
C
López-Gómez
Research Laboratory, UGCI Neurociencias Clínicas, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga/Universidad de Málaga, Málaga, Spain.
Begoña
B
Oliver-Martos
Research Laboratory, UGCI Neurociencias Clínicas, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga/Universidad de Málaga, Málaga, Spain.
María-Jesús
MJ
Pinto-Medel
Research Laboratory, UGCI Neurociencias Clínicas, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga/Universidad de Málaga, Málaga, Spain.
Margarita
M
Suardiaz
Department of Neurology, UGCI Neurociencias Clínicas, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga/Universidad de Málaga, Málaga, Spain.
Virginia
V
Reyes-Garrido
Department of Neurology, UGCI Neurociencias Clínicas, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga/Universidad de Málaga, Málaga, Spain.
Patricia
P
Urbaneja
Department of Neurology, UGCI Neurociencias Clínicas, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga/Universidad de Málaga, Málaga, Spain.
Óscar
Ó
Fernández
Research Laboratory, UGCI Neurociencias Clínicas, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga/Universidad de Málaga, Málaga, Spain.
Laura
L
Leyva
D000328:Adult; D015415:Biomarkers; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D016899:Interferon-beta / Q000009:adverse effects* / Q000627:therapeutic use; D019169:Jurkat Cells; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms / Q000097:blood / Q000187:drug effects / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000097:blood / Q000187:drug effects / Q000235:genetics*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000097:blood / Q000187:drug effects / Q000235:genetics*
D015415:Biomarkers; D020033:Protein Isoforms; D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D016899:Interferon-beta
INTERFERON; MULTIPLE SCLEROSIS