Defense Date

2015

Document Type

Thesis

Degree Name

Master of Science

Department

Biology

First Advisor

John J. Ryan, Ph.D.

Abstract

This study demonstrates original findings of statin effects on IL-33 stimulated mast cells. Statins are a class of drugs used to lower cholesterol production by targeting HMG CoA reductase. These commonly prescribed drugs have been shown to be immunomodulatory. In this study, we have found that pretreatment with statins has a variety of effects on IL-33 stimulated mast cells. Atorvastatin suppresses TNF and IL-6 production, while fluvastatin significantly enhances release of these proinflammatory cytokines in BMMCs. Although they have differing effects on cytokine production, both statins lowered ST2 expression on the cell surface, decreased cell viability, and enhanced expression of the transcription factor KLF2, a negative regulator of NFκB. Blocking isoprenylation by using geranylgeranyl transferase inhibitor, but not farnesyl transferase, mimicked the effects of atorvastatin, while neither mirrored the effect of fluvastatin. Furthermore, fluvastatin effects were not reversed by mevalonic acid, the product of HMG-CoA reductase. These data indicate that fluvastatin effects are distinct from its activities as an HMG CoA reductase inhibitor. Fluvastatin effects required the presence of stem cell factor (SCF), and were enhanced by increasing SCF concentrations. Finally, fluvastatin enhanced IL-33-induced cytokine production and neutrophil recruitment in vivo. Collectively, these data suggest that statins can alter the mast cell response, and that drug choice can have divergent effects on outcome.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

8-6-2015

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