Advisory Committee Chair
Etty Benveniste
Advisory Committee Members
Jim Collawn
Stuart Frank
Peter King
Fang-Tsyr Lin
Document Type
Dissertation
Date of Award
2008
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Microglia/macrophages are the main intrinsic immune effector cells and the first cell types that respond to a variety of CNS injures. They have important functions including secretion of cytokines/chemokines and antigen presentation, thereby regulating immune responses. Interferon-γ (IFN-γ) is a cytokine involved in many aspects of the immune response, and activates microglia/macrophages to express cell surface antigens such as class II MHC, and co-stimulatory molecules such as CD40. CD40 and class II MHC molecules play a critical role in immune reactivity such as antigen presentation and subsequent T cell activation. However, aberrant CD40 and class II MHC expression have been implicated in participating in many human diseases, particularly autoimmune and inflammatory diseases including type I diabetes, rheumatoid arthritis, Alzheimer’s disease and Multiple Sclerosis. Therefore, proper regulation of CD40 and class II MHC expression is important. Statins are 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase inhibitors that exert anti-inflammatory effects independent of their cholesterol-lowering actions. Statin therapy exerts beneficial pleiotropic effects in numerous autoimmune diseases which are associated with aberrant expression of class II MHC, CD40, and cytokines/chemokines. In this dissertation, we focused on characterizing the regulatory mechanisms of statins on CD40 and class II MHC expression, and we identified statins as potent inhibitors for CD40 and class II MHC expression. We demonstrated that statins inhibit iii IFN-γ-induced CD40 expression by suppression of STAT-1α, and altering transcriptional events at the CD40 promoter. Regarding class II MHC expression, statins inhibit IFN-γ- induced class II MHC expression by suppressing CIITA gene expression, which results from inhibiting the recruitment of transcription factors such as STAT-1α, IRF-1 and USF-1, and co-activators such as Brg-1 to the CIITA promoter. More interestingly, we found that Rho family protein prenylation is involved in IFN-γ inducible expression of CD40 and CIITA, and that statins inhibit Rho family protein activation, which contributes to their inhibitory effects on CD40 and CIITA expression. Collectively, these data indicate that statins affect the transcriptional program of the CD40 and CIITA genes, thereby inhibiting their expression. Our findings provide a better understanding of the molecular basis underlying the clinical benefits of statin therapy in autoimmune diseases and their role in anti-inflammatory responses.
Recommended Citation
Lee, Sun Jung, "Transcriptional Regulation Of Cd40 And Class Ii Mhc Molecules In Macrophages And Microglia By Statins" (2008). All ETDs from UAB. 3743.
https://digitalcommons.library.uab.edu/etd-collection/3743