Inhibition of phosphoinositide 3 kinase-Akt (protein kinase B)-nuclear factor-kappa B pathway by lovastatin limits endothelial-monocyte cell interaction.
Integrity of the blood-brain barrier is essential for the normal functioning of CNS. Its disruption contributes to the pathobiology of various inflammatory neurodegenerative disorders. We have shown that the HMG-CoA reductase inhibitor (lovastatin) attenuated experimental autoimmune encephalomyelitis (EAE, an inflammatory disease of CNS) in rodents by inhibiting the infiltration of mononuclear cells into the CNS. Here, using an in vitro system, we report that lovastatin inhibits endothelial-monocyte cell interaction by down-regulating the expression of vascular cell adhesion molecule-1 and E-selectin by inhibiting the phosphoinositide 3 kinase (PI3-kinase)/protein kinase B (Akt)/nuclear factor-kappa B (NF-kappaB) pathway in endothelial cells. It inhibits tumor necrosis factor alpha (TNFalpha)-induced PI3-kinase, Akt and NF-kappaB activation in these cells. Co-transfection of constitutively active forms of PI3-kinase and Akt reversed the lovastatin-mediated inhibition of TNFalpha-induced adhesion, as well as activation of NF-kappaB, indicating the involvement of the PI3-kinase/Akt pathway in the interaction of adhesion molecules and the process of adhesion. This study reports that lovastatin down-regulates the pathway affecting the expression and interaction of adhesion molecules on endothelial cells, which in turn restricts the migration and infiltration of mononuclear cells thereby attenuating the pathogenesis of inflammatory diseases.
Prasad
Ratna
R
Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA.
Giri
Shailendra
S
Nath
Narender
N
Singh
Inderjit
I
Singh
Avtar K
AK
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002450:Cell Communication / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008148:Lovastatin / Q000494:pharmacology*; D051379:Mice; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt