Interferon-beta regulates cytokines and BDNF: greater effect in relapsing than in progressive multiple sclerosis.
The mechanism of action of interferon (IFN)-beta therapy in multiple sclerosis (MS) is only partially known, and its efficacy changes with disease stage. In different forms of MS, we determined how IFN-beta regulates mononuclear cell production of the important anti-inflammatory Th2 cytokine - IL-10, the Th1 cytokine - IFN-gamma, and the brain-derived neurotrophic protein - BDNF. Activated T cells and monocytes from therapy-naïve patients secreted more IL-10 than healthy controls. During IFN-beta therapy, however, T cells produced less IL-10. In vitro, IFN-beta stimulated IL-10 production by activated T cells, but inhibited IL-10 secretion by activated monocytes, a richer source of IL-10 than T cells. The form of MS also affected cytokine production. IL-10 and BDNF levels in MNC were high during relapsing/remitting (RR) MS, but low in progressive MS. Surprisingly, IFN-beta therapy increased BDNF levels in antidepressant-naïve patients, but BDNF was lower during concurrent antidepressant drug therapy, suggesting an interaction between MS, depression, and neurodegeneration. IFN-beta in vitro strongly induced IL-10 and IFN-gamma in activated T cells in RRMS, but not in progressive MS, suggesting IFN resistance. IFN-beta effects are specific for disease state and immune subsets, possibly explaining why IFN-beta therapy is most effective in early T cell-regulated RRMS, but less beneficial in progressive MS, where chronic plaques contain few T cells and high numbers of monocytes.
Hamamcioglu
K
K
Department of Neurology, Gülhane Military Medical Academy, Etlik, Ankara 06018, Turkey.
Reder
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D001402:B-Lymphocytes / Q000276:immunology*; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D016207:Cytokines / Q000502:physiology*; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000378:metabolism / Q000502:physiology; D008213:Lymphocyte Activation; D016131:Lymphocyte Subsets / Q000276:immunology; D020528:Multiple Sclerosis, Chronic Progressive / Q000276:immunology / Q000503:physiopathology*; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000276:immunology / Q000503:physiopathology*; D013601:T-Lymphocytes / Q000276:immunology*
D019208:Brain-Derived Neurotrophic Factor; D016207:Cytokines; D016753:Interleukin-10; D016899:Interferon-beta; D007371:Interferon-gamma