A Rational Insight into the Effect of Dimethyl Sulfoxide on TNF-? Activity.

ABSTRACT: Direct inhibition of tumor necrosis factor-alpha (TNF-?) action is considered a promising way to prevent or treat TNF-?-associated diseases. The trimeric form of TNF-? binds to its receptor (TNFR) and activates the downstream signaling pathway. The interaction of TNF-? with molecular-grade dimethyl sulfoxide (DMSO) in an equal volumetric ratio renders TNF-? inert, in this state, TNF-? fails to activate TNFR. Here, we aimed to examine the inhibition of TNF-? function by various concentrations of DMSO. Its higher concentration led to stronger attenuation of TNF-?-induced cytokine secretion by fibroblasts, and of their death. We found that this inhibition was mediated by a perturbation in the formation of the functional TNF-? trimer. Molecular dynamics simulations revealed a transient interaction between DMSO molecules and the central hydrophobic cavity of the TNF-? homodimer, indicating that a brief interaction of DMSO with the TNF-? homodimer may disrupt the formation of the functional homotrimer. We also found that the sensitizing effect of actinomycin D on TNF-?-induced cell death depends upon the timing of these treatments and on the cell type. This study will help to select an appropriate concentration of DMSO as a working solvent for the screening of water-insoluble TNF-? inhibitors.

SUBMITTER: Javaid N 

PROVIDER: S-EPMC7763846 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature