Potential interplay between NFκB and PPARγ in human dermal microvascular endothelial cells cultured in low magnesium

Abstract

Dermal microvascular endothelial cells contribute to cutaneous inflammation by secreting proinflammatory cytokines and chemokines. We show here that low extracellular magnesium stimulates the secretion of interleukin 8 and monocyte chemoattractant protein-1 in dermal microvascular endothelial cells. This secretory pattern might result from interplay between NFB, the master regulator of inflammation, and PPAR␥, a transcription factor that has emerged as an inhibitor of inflammation. Indeed, both NFB and PPAR␥ are activated in dermal microvascular endothelial cells cultured in low magnesiumcontaining medium. In conclusion, we hypothesize that PPAR␥ and NFB might contribute to the response of these cells to low Mg.

TWEAK/Fn14 Activation Participates in Skin Inflammation

“…These diseases are characterized by inflammatory reactions directed at small vessels, in which the damage to dermal microvascular endothelial cells is usually the primary event. Dermal microvascular endothelial cells can produce TNF- α , MCP-1, IL-1 α , IL-1 β , IL-6, and IL-8, which are fundamental in inflammation and angiogenesis [ 61 ].…”

Burning magnesium, a sparkle in acute inflammation: gleams from experimental models

“…Accordingly, physiologic or high extracellular concentrations of Mg exert anti-inflammatory properties. In cultured endothelial cells high Mg inhibits NF-kB and prevents the release of inflammatory mediators and cytokines [42], while in neutrophils and macrophages Mg inhibits oxidative burst [53,54]. Moreover, high extracellular Mg reduces the release of inflammatory cytokines from leukocytes [55] and the levels of Toll-like receptor (TLR) 4 in sebocytes [56].…”

“…They secrete various molecules mediating vasodilatation and permeabilization such as prostacyclin and nitric oxide, and release cytokines and chemokines that facilitate the recruitment of leukocytes. In response to low extracellular Mg, cultured microvascular endothelial cells activate NF-kB, which induces the expression of a large array of pro-inflammatory proteins [42]. Mg deficiency upregulates cell-surface adhesion molecules, which renders the endothelium adhesive for leukocytes [43], and the chemokines IL-8 and monocyte chemoattractant protein-1 (MCP-1/CCL2) [42].…”

“…Moreover, cells cultured in low extracellular Mg produce high levels of IL-10 [47], which represses pro-inflammatory responses and limits unnecessary tissue disruptions. In microvascular endothelial cells, low extracellular Mg rapidly activates NF-kB partly through the overproduction of ROS, but later it also activates peroxisome proliferator-activated receptor (PPAR)γ [42], probably through the induction of eicosanoids. PPARγ inhibits NF-kB by complexing with NF-kB subunits and shuttling them from the nucleus to the cytoplasm [42].…”

“…In microvascular endothelial cells, low extracellular Mg rapidly activates NF-kB partly through the overproduction of ROS, but later it also activates peroxisome proliferator-activated receptor (PPAR)γ [42], probably through the induction of eicosanoids. PPARγ inhibits NF-kB by complexing with NF-kB subunits and shuttling them from the nucleus to the cytoplasm [42]. We argue that the activation of PPARγ in low Mg tips the balance towards the resolution of inflammation (figure 3).…”