The balance of pro-inflammatory and trophic factors in multiple sclerosis patients: effects of acute relapse and immunomodulatory treatment

Background: In multiple sclerosis inflammation is primarily injurious to the central nervous system, but its therapeutic suppression might inhibit repair-promoting factors. Objectives: We aimed at better describing the complexity of biological effects during an acute relapse and analysed the effects of intervention with high-dose i.v. glucocorticoids and immunomodulatory treatment with interferon-beta (IFN beta). Methods: We studied the intracellular expression levels of the pro-inflammatory mediators tumour necrosis factor alpha (TNF alpha) and inducible nitric oxide synthase (iNOS) together with the neurotrophins ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) in freshly isolated peripheral blood mononuclear cells of multiple sclerosis patients during an acute relapse, after intervention with i.v. methylprednisolone and at baseline, using a highly quantitative flow-cytometric approach. Results: We demonstrated the expression of CNTF in human leucocytes. We showed that CNTF levels differed in acutely relapsing multiple sclerosis patients compared with controls and increased after corticosteroid treatment. CNTF can counteract the toxicity of TNF alpha towards oligodendrocytes and we found TNF alpha increased during acute relapses. Following corticosteroids, neither TNF alpha nor iNOS expression was reduced. Levels of BDNF were not affected by glucocorticoids, but increased during IFN beta therapy. However, IFN beta also increased the expression of iNOS and major histocompatibility complex class I (MHC-I), underlining its immunomodulatory potential. Conclusions: Multiple sclerosis patients might benefit from reparative, and not solely from anti-inflammatory, effects of glucocorticoids. Interactive effects of glucocorticoid- and IFN beta-treatment need to be considered to improve neuroprotection and remyelination resulting from immunomodulatory treatment.