Selenium supplementation induces metalloproteinase-dependent L-selectin shedding from monocytes.
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.
Ahrens
Ingo
I
Department of Cardiology and Angiology, University Hospital of Freiburg, Freiburg, Germany.
Ellwanger
Christoph
C
Smith
Belinda K
BK
Bassler
Nicole
N
Chen
Yung Chih
YC
Neudorfer
Irene
I
Ludwig
Andreas
A
Bode
Christoph
C
Peter
Karlheinz
K
D051722:ADAM Proteins / Q000502:physiology; D000072198:ADAM17 Protein; D002448:Cell Adhesion; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019587:Dietary Supplements; D006801:Humans; D019041:L-Selectin / Q000378:metabolism*; D036904:Leukocyte Rolling; D045726:Metalloproteases / Q000502:physiology*; D009000:Monocytes / Q000378:metabolism*; D012643:Selenium / Q000008:administration & dosage*; D018805:Sepsis / Q000188:drug therapy; D033081:Shear Strength; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D019041:L-Selectin; D045726:Metalloproteases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; D012643:Selenium; D013755:Tetradecanoylphorbol Acetate