The H2S Donor GYY4137 Stimulates Reactive Oxygen Species Generation in BV2 Cells While Suppressing the Secretion of TNF and Nitric Oxide

Abstract

GYY4137 is a hydrogen sulfide (H2S) donor that has been shown to act in an anti-inflammatory manner in vitro and in vivo. Microglial cells are among the major players in immunoinflammatory, degenerative, and neoplastic disorders of the central nervous system, including multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, and glioblastoma multiforme. So far, the effects of GYY4137 on microglial cells have not been thoroughly investigated. In this study, BV2 microglial cells were stimulated with interferon-gamma and lipopolysaccharide and treated with GYY4137. The agent did not influence the viability of BV2 cells in concentrations up to 200 μM. It inhibited tumor necrosis factor but not interleukin-6 production. Expression of CD40 and CD86 were reduced under the influence of the donor. The phagocytic ability of BV2 cells and nitric oxide production were also affected by the agent. Surprisingly, GYY4137 upregulated generation of reactive oxygen species (ROS) by BV2 cells. The effect was mimicked by another H2S donor, Na2S, and it was not reproduced in macrophages. Our results demonstrate that GYY4137 downregulates inflammatory properties of BV2 cells but increases their ability to generate ROS. Further investigation of this unexpected phenomenon is warranted.

Upregulation of Tolerogenic Pathways by the Hydrogen Sulfide Donor GYY4137 and Impaired Expression of H2S-Producing Enzymes in Multiple Sclerosis

“…Specifically, the protective effects of H 2 S in neurons and astrocytes that have been reported [59,60] suggest that this molecule could be beneficial in MS. Along the same line, we and others have previously shown that H 2 S potently affects the inflammatory activity of microglia [39,47]. However, the effect of H 2 S on encephalytogenic cells during MS and EAE has not been addressed.…”

“…Murine BMDCs were differentiated in vitro in the presence of GM-CSF and matured under the influence of LPS. GYY4137 (200 M) was applied simultaneously with LPS for 24 h. The dose of 200 M was chosen as it was previously shown to be efficient in modulating the phenotypic and functional properties of microglial cells [ 47 ] without affecting cell viability. Indeed, at this dose, GYY4137 did not affect the DC viability ( Figure 1 A).…”

“…In our previous paper, we have shown that GYY4137 down-regulated TNF and NO secretion, as well as CD40 and CD86 co-stimulatory molecule expression, in microglial cells [47]. In this study, we extended our area of research in MS to the effect of GYY4137 on DCs and T cells that are involved in the initiation and maintaining of the pathogenesis of MS and EAE.…”

Impaired Expression of Tetraspanin 32 (TSPAN32) in Memory T Cells of Patients with Multiple Sclerosis

“…We also studied the possible diagnostic and prognostic value of TSPAN32 expression in PBMC of MS patients, on the course of the disease. The use of whole-genome expression databases has been largely exploited [25][26][27][28] for the characterization of pathogenic pathways and to identify therapeutic targets for a variety of disorders, including immunoinflammatory and autoimmune diseases [29][30][31][32][33][34][35][36], cancer [37][38][39], and has allowed dismantling pathogenetic pathways [40][41][42], along with the identification of novel tailored therapeutic targets [43][44][45][46].…”

In Silico and In Vivo Analysis of IL37 in Multiple Sclerosis Reveals Its Probable Homeostatic Role on the Clinical Activity, Disability, and Treatment with Fingolimod

“…In the present study, we first analyzed the expression levels of IL37, SIGIRR, and IL18R1 in circulating immune cells from MS patients. In particular, we performed a DNA microarray analysis that represents a useful in silico tool for the better understanding of pathogenic pathways and the possible prediction of novel diagnostic therapeutic strategies, as it has been shown in a variety of clinical settings, such as autoimmune and immunoinflammatory diseases [38][39][40][41][42][43][44] and cancer [45][46][47][48][49][50][51], leading to the identification of novel therapeutic targets [52][53][54][55].…”