Selenium supplementation induces metalloproteinase-dependent L-selectin shedding from monocytes

Abstract

Selenium therapy in patients with severe sepsis improves clinical outcome and has been associated with increased activity of the selenoprotein glutathione peroxidase. However, the mechanism of the observed beneficial effects remains unclear. We determined the effect of selenium treatment on the monocyte adhesion molecule L-selectin and L-selectin-related monocyte functions in vitro and transferred our findings to an in vivo mouse model. Monocytes were purified, cultured, and incubated in the presence or absence of supplemented selenium and metalloproteinase (MP) inhibitors for up to 16 h. Expression of L-selectin was unaffected after 2 and 6 h but decreased after 16 h of incubation in the presence of selenium. Soluble L-selectin (sL-selectin) in the supernatant was determined by ELISA. A 2.3-fold increase as a result of shedding of L-selectin was observed after 16 h of selenium treatment. Addition of the MP inhibitors GM6001, TNF-alpha-converting enzyme inhibitor 2, or GW280264X strongly reduced selenium-induced L-selectin shedding, indicating a MP-dependent mechanism. The functional consequences of L-selectin shedding were examined in a flow chamber model. Selenium-treated monocytes showed significantly decreased rolling and adhesion to the L-selectin ligand Sialyl-Lewis(a) under conditions of venous shear stress (0.5 dyne/cm(2)). Selenium treatment of C57BL6 mice led to increased serum levels of sL-selectin, underscoring the in vivo relevance of our findings. We describe a selenium-induced down-regulation of L-selectin on monocytes as a consequence of MP-dependent shedding of this membrane-anchored adhesion molecule. The impairment of monocyte adhesion by selenium supplementation may represent an important, underlying mechanism for the modulation of inflammatory reactions in patients with severe sepsis.

Influence of ISDN, l-NAME and selenium on microcirculation, leukocyte endothelium interaction and angiogenesis after frostbite

“…Contrary to expectations, no significant positive results could be observed in our study. Selenium was shown to reduce the number of rollers and stickers in vitro, which might be part of its anti-inflammatory capabilities [29]. In our study, these numbers did not differ significantly from the control group.…”

“…While such anti-inflammatory properties might be beneficial for the organism as a whole to reduce the damage by free radicals and the modulation of the (dysregulated) autoimmune response (e.g. in SIRS), these effects might hamper the local wound healing by suppression of cell interaction, migration and phagocytosis [29][30][31]. These effects at least partly explain the low functional vessel density and the significant lower angiogenesis in comparison to the control group.…”

Slit2 Prevents Neutrophil Recruitment and Renal Ischemia-Reperfusion Injury

“…Calcein-labeled human neutrophils (3310 5 /well) were preincubated with Slit2 (4.5 mg/ml) for 10 minutes and then perfused through the channels at a shear rate of 0.5 dynes/cm 2 . 94,95 In some experiments, Slit2 (4.5 mg/ml) was premixed with molar equivalent amounts of RoboN for 10 minutes at 37°C before incubating with neutrophils. The plates were placed on the heated stage of a Nikon TE2000 inverted microscope and visualized using a 203 objective.…”

Prednisolone but not selenium and rtPA reduces edema and improves angiogenesis after burn in mice

“…While such anti-inflammatory properties might be beneficial for the organism as a whole to reduce the damage by free radicals and the modulation of the (dysregulated) autoimmune response (e.g. in SIRS), these effects might hamper the local wound healing by suppression of cell interaction, migration and phagocytosis [36][37][38]. These effects at least partly explain the low functional vessel density and the significant lower angiogenesis in comparison to the control group.…”

“…Selenium showed positive results in burns [6,35] and a reduction of the number of rollers and stickers in vitro, which might be part of its anti-inflammatory capabilities [36]. Contrary to expectations, no significant positive results could be seen over the entire course of observation.…”