The Anti-Inflammatory Effects of Dimethyl Fumarate in Astrocytes Involve Glutathione and Haem Oxygenase-1

Abstract

DMF (dimethyl fumarate) exerts anti-inflammatory and pro-metabolic effects in a variety of cell types, and a formulation (BG-12) is being evaluated for monotherapy in multiple sclerosis patients. DMF modifies glutathione (GSH) levels that can induce expression of the anti-inflammatory protein HO-1 (haem oxygenase-1). In primary astrocytes and C6 glioma cells, BG-12 dose-dependently suppressed nitrite production induced by either LI [LPS (lipopolysaccharide) at 1 μg/ml plus IFNγ (interferon γ) at 20 units/ml] or a mixture of pro-inflammatory cytokines, with greater efficacy in C6 cells. BG-12 reduced NOS2 (nitric oxide synthase 2) mRNA levels and activation of a NOS2 promoter, reduced nuclear levels of NF-κB (nuclear factor κB) p65 subunit and attenuated loss of IκBα (inhibitory κBα) in both cell types, although with greater effects in astrocytes. In astrocytes, LI decreased mRNA levels for GSHr (GSH reductase) and GCL (c-glutamylcysteine synthetase), and slightly suppressed GSHs (GSH synthetase) mRNAs. Co-treatment with BG-12 prevented those decreased and increased levels above control values. In contrast, LI reduced GSHp (GSH peroxidase) and GCL in C6 cells, and BG-12 had no effect on those levels. BG-12 increased nuclear levels of Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2), an inducer of GSH-related enzymes, in astrocytes but not C6 cells. In astrocytes, GSH was decreased by BG-12 at 2 h and increased at 24 h. Prior depletion of GSH using buthionine-sulfoximine increased the ability of BG-12 to reduce nitrites. In astrocytes, BG-12 increased HO-1 mRNA levels and effects on nitrite levels were blocked by an HO-1 inhibitor. These results demonstrate that BG-12 suppresses inflammatory activation in astrocytes and C6 glioma cells, but with distinct mechanisms, different dependence on GSH and different effects on transcription factor activation.

Nuclear Factor–Erythroid-2–Related Factor 2 in Aging and Lung Fibrosis

“…An oral formulation of the chemical inducer dimethyl fumarate (commonly known as BG-132), US Food and Drug Administration approved for the treatment of multiple sclerosis, exerts antiinflammatory effects through the activation of the Nrf2 pathway. 128 Dibenzoylmethane, an analog of curcumin, has been shown to activate the Nrf2-mediated detoxification pathway and inhibits benzo(a)pyrene-induced DNA adduct formation in lungs. 129 Induction of Nrf2 with the triterpenoid CDDO-imidazolide (bardoxolone) and its analogs attenuates cigarette smokeeinduced emphysema and cardiac dysfunction in mice, 118 and diabetic nephropathy in preclinical models.…”

Glutathione in multiple sclerosis: More than just an antioxidant?

“…Monomethylfumarate is a well-known Nrf2 activator and was demonstrated to enhance glutathione levels, and increased both cellular antioxidant and anti-inflammatory potential, in a Nrf2-dependent manner. [40][41][42] Recent clinical trials with oral dimethylfumarate (Tecfidera ® on the pharmaceutical market) clearly highlight the therapeutic potential of Nrf2 activation in MS (review, Fox et al 43 ).…”

Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a

“…13 In addition, DMF reduces the nuclear factor NF-kB in astrocytes and C6 cells, inhibits the degradation of IkBa, and reduces the expression of nitric oxide synthase 2. 14 In the experimental autoimmune encephalomyelitis model, DMF exerts clinical effects through the reduction of macrophage-induced inflammation in the spinal cord. 15 In addition, DMF inhibits dendritic cell (DC) maturation through a reduction in the release of the inflammatory cytokines IL-6 and IL-12.…”