Interferon beta-1a increases leukocyte TNF-R1 and decreases TNF-R2 gene expression in human MS therapy responders, thus TNF-a signalling via TNF-R1 might be beneficial, via TNF-R2 detrimental

Introduction: Tissue specifically expressed tumor necrosis factor receptors 1 and 2 (TNF-R1/2) transduce apoptosis or inflammation (Hsu, 1996). In a case, R1 mediates apoptosis in contrast to R2 (Shimizu et al., 2005). Neutralizing TNF-a, e.g. by lenercept, lead to clinical or subclinical relapses.

Objective: To investigate the influence of IFN beta-1a on leukocyte TNF-R1 and -R2 gene expression in RR-MS patients.

Methods: 53 RR-MS patients were observed (open parallel-group study, 1 year). Every 2nd day, 26 therapy starters were treated with 22 ug IFN beta-1a (T). The MS control group (C) comprised 27 patients, the healthy control group (HC) 25 patients. By quantitative RT-PCR we measured leukocyte TNF-R1/2-mRNA relative to an internal standard. Clinical therapy responders (no relapse) and clinical nonresponders (at least 1 relapse) or MRI responders (>=10% reduction of T2-lesion load; MRs) and nonresponders (<10%; NMRs) were determined. MRIs were analyzed semiquantitatively. Values: medians. U test (p<0.05 significant). rs=Spearman's correlation coefficient.

Results: At baseline, TNF-R1/2-mRNA was significantly lower (p=0.012 and p=0.011) in T and C compared to HC. A correlation existed between EDSS and R1-mRNA (rs=0.535). Between month 0 and 12, R1-mRNA rised from 339.11 to 390.46 (p=0.083) in T and decreased from 250.09 to 193.60 (p=0.145) in C. The difference was significant (p=0.009). In T, the difference between month 0 and month 12 T2 lesion load correlated negatively with the difference between month 0 and 12 R1-mRNA (rs=-0.618). In clinical responders, TNF-R1-mRNA increased significantly by 358,5 (p<0.001) and TNF-R2-mRNA decreased by 28,1 (p=0.033). In MRI responders, R1-mRNA increased significantly by 419,7 (p=0.007) and R2-mRNA decreased by 14,1 (p=0.108). Nonresponders showed no significant changes. Except for R2-mRNA in MRs and NMRs, responder and nonresponder changes were significantly different.

Conclusion: Results might support an important role of TNF-R1/2 in leukocyte apoptosis: at beginning of MS, TNF-R1 expression is low, little leukocyte apoptosis occurs resulting in relapses. In HC or later in MS, TNF-R1 expression is higher. If under IFN therapy expression of TNF-R1 is increased and that of TNF-R2 is diminished, an increase of leukocyte apoptosis might promote a better clinical and notably also subclinical outcome. Lenercept results agree. Further investigations are needed to clarify the details including translation and signal transduction.

Figure 1–4: Difference between month 0 and month 12 relative TNF-R1 or TNF-R2 gene expression is depicted on the ordinate

Figure 1: Change in the relative TNF-R1 gene expression over 1 year for clinical responders (CRs; n=10) and clinical nonresponders (NCRs; n=16) under IFN beta-1a therapy.

Figure 2: Change in the relative TNF-R2 gene expression over 1 year for CRs (n=10) and NCRs (n=16) under IFN beta-1a therapy.

Figure 3: Change in the relative TNF-R1 gene expression over 1 year for MRI responders (MRs; n=8) and MRI nonresponders (NMRs; n=8) under IFN beta-1a therapy.

Figure 4: Change in the relative TNF-R2 gene expression over 1 year for MRI responders (MRs; n=8) and MRI nonresponders (NMRs; n=8) under IFN beta-1a therapy.