Interferon beta-1b treatment modulates TNFα and IFNγ spontaneous gene expression in MS

Abstract

Background: Interferon beta (IFNβ) lessens the overall frequency of acute attacks in patients with the relapsing-remitting form of multiple sclerosis (RRMS). IFNβ may act by decreasing the synthesis of inflammatory cytokines. Objectives: To determine whether IFNβ-1b treatment had an initial and sustained effect on the in vivo synthesis and secretion of tumor necrosis factor α (TNFα) and IFNγ. Methods: A highly sensitive reverse-transcriptase PCR technique was used to measure baseline levels of mRNA in freshly isolated cells from patients before therapy and at 3, 6, and 12 months of treatment. Also, protein concentration was measured in serum and in culture supernatants from mitogen-stimulated cells. The authors studied 16 patients, of whom 11 did not have clinical exacerbations, whereas 5 had one clinical relapse each during the study. Results: Mean values of TNFα mRNA levels in the 11 stable patients decreased significantly at 3 and 6 months of treatment in comparison with initial data. After 6 months of therapy, IFNβ-1b downmodulated TNFα transcripts in the 5 patients who experienced relapse. In this group of patients, TNFα levels rose sharply to reach pretreated values at 1 year of IFNβ-1b treatment. At the beginning of therapy, 6 patients had high concentrations of serum TNFα, which decreased to normal values following IFNβ-1b therapy. IFNγ mRNA expression also diminished after 6 and 12 months of IFNβ-1b therapy in the group of stable patients, whereas nonrelevant variations were observed in patients who had one relapse. Initially, patients’ peripheral mononuclear cells secreted diminished amounts of TNFα and IFNγ on PHA + PMA mitogen stimulation in comparison with normal control subjects. After 1 year of therapy, IFNβ-1b restored the normal production of TNFα, whereas therapy did not restore IFNγ secretion to control values. Conclusion: IFNβ-1b decreases the spontaneous expression of two proinflammatory cytokines.