Interferon β-1a Induces Tumor Necrosis Factor Receptor 1 but Decreases Tumor Necrosis Factor Receptor 2 Leukocyte mRNA Levels in Relapsing-Remitting Multiple Sclerosis

Abstract

Objective: Members of the tumor necrosis factor (TNF) receptor superfamily play a major role in the pathogenesis of multiple sclerosis. To elucidate the role of TNF receptors, in 53 relapsing-remitting multiple sclerosis patients, we measured the TNF receptor 1 and receptor 2 (TNF-R1 and TNF-R2) mRNA levels in peripheral blood leukocytes in natural history (n = 27) and during administration of interferon (IFN) β-1a (n = 26). Methods: Every 3 months for the duration of 1 year peripheral blood leukocytes were investigated by quantitative reverse transcription polymerase chain reaction. Every 6 months, MRI scans of the brain were analyzed semiquantitatively. Results: At baseline, clinical expanded disability status scale score and TNF-R1 mRNA level were correlated. In the therapy group, the difference between T2 lesion load at baseline and after 12 months correlated negatively with the difference between TNF-R1 mRNA level at baseline and after 12 months. Subcutaneously applied IFN β increased the amount of TNF-R1 mRNA, but partly decreased the amount of TNF-R2 mRNA in clinically and subclinically defined responders to therapy after 1 year compared to baseline. Conclusion: This result might support the notion that due to different signal transduction properties of both receptors in the natural course of multiple sclerosis, TNF-α signaling in leukocytes via TNF-R1 might be beneficial, but detrimental via proinflammatory TNF-R2: part of the therapeutic efficacy of current first-line standard therapy with IFN might be due to the modulation of signal transduction pathways.

TRAF2 is Upregulated in Relapsing-Remitting Multiple Sclerosis

“…Collated with our previous results [15] demonstrating a correlation between TNFR1 mRNA and EDSS in RRMS and thus low TNFR1 expression at the beginning of the disease, and the finding that subcutaneously applied IFN-β increased the amount of TNF-R1 mRNA but partly decreased the amount of TNF-R2 mRNA in clinically and subclinically defined responders to therapy after 1 year compared to baseline levels, the following may be suggested: TRAF2 elevation in RRMS might reflect enhanced proinflammatory signaling by TNFR1, and in particular by TNFR2, which primarily adopts a proinflammatory involvement in leukocytes. Taking the results of Arnett et al [26] into account, which indicate that TNFR2 is critical for oligodendrocyte regeneration, the combination of differential expression values of TRAF2 in CNS tissue and blood leukocytes in MS might run entirely contrary to the result shown for systemic lupus erythematosus, each time taking into account the respective state of the disease.…”

“…In our recent study, in RRMS, we revealed a correlation between the expanded disability status scale (EDSS) score and the TNF-R1 mRNA level in leukocytes. Additionally, subcutaneously applied IFN-β increased the amount of TNF-R1 mRNA, but partly decreased TNF-R2 mRNA expression in clinically and subclinically defined responders to therapy after 1 year compared to the baseline value [15]. We performed quantitative reverse transcription polymerase chain reaction (RT-PCR) to investigate leukocyte TRAF2 and RIP expression in MS patients for the first time.…”

Effects of Interferon β-1a and Interferon β-1b Monotherapies on Selected Serum Cytokines and Nitrite Levels in Patients with Relapsing-Remitting Multiple Sclerosis: A 3-Year Longitudinal Study

“…IFNγ and TNFα are usually deemed proinflammatory. However, there is also evidence for a double-sided ‘Janus' role of both TNFα and IFNγ in chronic autoimmune inflammation and MS [66,70,71,72], and it has been proposed that the TNFα/IL-6 balance is of importance for the therapeutic effect of the IFNβ treatments [73]. The relationship between changes in EDSS scores and IFNγ/IL-6 ratio in our study groups (compare fig.…”

FADD Is Upregulated in Relapsing Remitting Multiple Sclerosis

“…Taking into account several roles of FADD [8] collated with our previous results [15], this may suggest the following notion: FADD elevation in RR MS might reflect enhanced proinflammatory signaling in peripheral blood leukocytes, but at later stages of the disease or in SP MS TNFR1 signaling that is then predominant rather signals apoptosis. …”

“…In multiple sclerosis (MS), a reduction in leukocyte apoptosis might contribute to enhanced migration of autoreactive T cells into the CNS and perpetuation of inflammation [14], resulting in clinical and subclinical exacerbations. Recently, we have succeeded in demonstrating that in natural history in relapse remitting (RR) MS there is a correlation between the expanded disability status scale (EDSS) score and the TNF-R1 mRNA level in leukocytes [15]. Here, we performed quantitative reverse transcription polymerase chain reaction (RT-PCR) to investigate leukocyte TRADD and FADD expression in MS patients for the first time.…”