Suppression of LPS-induced inflammatory responses by the hydroxyl groups of dexamethasone

Abstract

The innate immune response is a central process that is activated during pathogenic infection in order to maintain physiological homeostasis. It is well known that dexamethasone (Dex), a synthetic glucocorticoid, is a potent immunosuppressant that inhibits the cytokine production induced by bacterial lipopolysaccharides (LPS). Nevertheless, the extent to which the functional groups of Dex control the excessive activation of inflammatory reactions remains unknown. Furthermore, importantly, the role of Dex in the innate immune response remains unclear. Here we explore the mechanism of LPS-induced TNF-α secretion and reveal p38 MAPK signaling as a target of Dex that is involved in control of tumor necrosis factor-α (TNF-α)-converting enzyme (TACE) activity; that later mediates the shedding of TNF-α that allows its secretion. We further demonstrate that the 11-hydroxyl and 21-hydroxyl groups of Dex are the main groups that are involved in reducing LPS-induced TNF-α secretion by activated macrophages. Blockage of the hydroxyl groups of Dex inhibits immunosuppressant effect of Dex during LPS-induced TNF-α secretion and mouse mortality. Our findings demonstrate Dex signaling is involved in the control of innate immunity.

Therapeutic Potential of Rhododendron arboreum Polysaccharides in an Animal Model of Lipopolysaccharide-Inflicted Oxidative Stress and Systemic Inflammation

“…To treat gram-negative sepsis effectively with therapeutic strategies directed against potentially injurious endogenous factors, it is imperative to recognize the temporal expression of these endogenous factors in vivo. For example, dexamethasone is a potent inhibitor of LPS-stimulated TNF-α production, suppressing TNF-α synthesis and release both at the transcriptional and post-transcriptional levels [ 35 ]. However, dexamethasone has proved to be poorly effective in treating septic shock in clinical studies [ 35 , 36 ].…”

“…For example, dexamethasone is a potent inhibitor of LPS-stimulated TNF-α production, suppressing TNF-α synthesis and release both at the transcriptional and post-transcriptional levels [ 35 ]. However, dexamethasone has proved to be poorly effective in treating septic shock in clinical studies [ 35 , 36 ]. This difference in effect is at least partially associated with the rapid temporal expression of TNF-α and the time of administration of dexamethasone.…”

A comprehensive guide to the pharmacologic regulation of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 entry receptor

“…Of note, budesonide, a glucocorticoid, activates ADAM17 in bronchial epithelial cells ( Zijlstra et al, 2014 ). However, dexamethasone inhibited ADAM17 activity without affecting its expression level in lipopolysaccharide-activated RAW cells ( Chuang et al, 2017 ).…”

Phyllanthus amarus prevents LPS-mediated BV2 microglial activation via MyD88 and NF-κB signaling pathways

“…Although EPA inhibited iNOS and TNFα similarly at all concentrations, further investigations looking into the gene expression level are required to further explain the lack of dosedependent effects on expression of these proteins. Dexamethasone is a potent immunosuppressant that inhibits the cytokine production induced by bacterial lipopolysaccharides [62]. Therefore, it was able to reduce the expression of a majority of marker proteins near to the control levels in the treated cultures.…”