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

Nasir Javaid,Hana Seo,Farzana Yasmeen,Sangdun Choi,Mahesh Chandra Patra

doi:10.3390/ijms21249450

Abstract

Direct inhibition of tumor necrosis factor-alpha (TNF-α) action is considered a promising way to prevent or treat TNF-α-associated diseases. The trimeric form of TNF-α binds to its receptor (TNFR) and activates the downstream signaling pathway. The interaction of TNF-α with molecular-grade dimethyl sulfoxide (DMSO) in an equal volumetric ratio renders TNF-α inert, in this state, TNF-α fails to activate TNFR. Here, we aimed to examine the inhibition of TNF-α function by various concentrations of DMSO. Its higher concentration led to stronger attenuation of TNF-α-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-α trimer. Molecular dynamics simulations revealed a transient interaction between DMSO molecules and the central hydrophobic cavity of the TNF-α homodimer, indicating that a brief interaction of DMSO with the TNF-α homodimer may disrupt the formation of the functional homotrimer. We also found that the sensitizing effect of actinomycin D on TNF-α-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-α inhibitors.

Highlights

Multiple proinflammatory cytokines are members of the tumor necrosis factor (TNF) superfamily and are involved in several physiological processes, including tumor prevention and host protection [1,2]
TNF-α is produced by various immune cells and activates nuclear factor κ-light-chain enhancer of activated B cells (NF-κB) and mitogen-activated protein kinases (MAPKs) via its receptors (TNFR1 and TNFR2), thereby leading to the production of multiple inflammatory cytokines [38,39,40,41]
The mixture was incubated with human dermal fibroblasts (HDFs) for 24 h, which converted the final concentration of dimethyl sulfoxide (DMSO) to 0.0005%, 0.005%, 0.05%, 0.25%, and 0.5%, respectively

Summary

Introduction

Multiple proinflammatory cytokines are members of the tumor necrosis factor (TNF) superfamily and are involved in several physiological processes, including tumor prevention and host protection [1,2]. TNF is a homo-trimeric cellular cytokine that is converted into a soluble form via proteolytic cleavage of the transmembrane form. The trimeric form of both soluble and transmembrane TNF interacts with TNF receptor I and/or II to bring some conformational changes to their complex, which leads to the activation of downstream signaling pathways [11,12,13,14]. At physiological concentrations (pg/mL–ng/mL), soluble TNF is unstable in serum or buffer and converts itself into a reversible inactive monomeric form [15,16,17]. The oligomeric form of TNF-α is disturbed by certain solvents, such as dimethyl sulfoxide (DMSO) [16,19]

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