Graduation Date

Fall 12-18-2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmacology and Experimental Neuroscience

First Advisor

Pawel Ciborowski

Abstract

The effects of methamphetamine (Meth) in the periphery are not well studied and a comprehensive investigation on the effects and molecular mechanism will give insight into why Meth users are at an increased risk of infections. For this reason, we use macrophages as a model for the immune system dysregulation seen in Meth abusers and also because macrophages are a long-lived cell that HIV infects and persists in. We aimed to determine the effects of Meth on the cytokine production, histone modifying enzymes and the corresponding histone post-translational modifications, and the molecular mechanism in HIV-infected human macrophages treated with combination antiretroviral therapy.

We measured a total of six histone deacetylases (HDACs) and found that Meth decreases HDAC1 but not in HIV or HIV and Meth. Combinational antiretroviral therapy also did not seem to have an effect on any HDACs measured. The decrease in HDAC1 correlated to an increase in acetylation of HDAC1 histone targets, histone 4 lysine 5 and histone 3 lysine 18. Next, we determined that Meth induces a time-dependent and concentration dependent change in cytokine expression. Furthermore, Meth generated a rapid induction of pro-inflammatory cytokines at two hours and maintained until 6 hours post exposure. Subsequently, we expanded on where Meth could be affecting the TLR9 signaling pathway to support the result of altered cytokine production by looking at DNA methylation, presence of transcription factors, and TLR9-mediated signaling mediators.

In conclusion, Meth decreases HDAC1, modifies cytokine production in macrophages leading to a pro-inflammatory phenotype.

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