Date Available
12-9-2015
Year of Publication
2015
Document Type
Doctoral Dissertation
Degree Name
Doctor of Philosophy (PhD)
College
Medicine
Department/School/Program
Microbiology, Immunology, and Molecular Genetics
Advisor
Dr. Joseph P. McGillis
Co-Director of Graduate Studies
Dr. Donald Cohen
Abstract
Transcription factors regulate distinct macrophage functions by regulating gene expression in response to micro-environmental cues. This functional plasticity is critical for regulating innate and adaptive immune responses during infection and during chronic disease processes including inflammatory diseases and cancer. Microarray analysis of macrophages polarized to a pro-inflammatory (M1) phenotype with LPS and IFNγ revealed that basic leucine zipper transcription factor ATF-like 2 (Batf2), a member of the AP1 transcription factors, is selectively upregulated in M1 macrophages compared to anti-inflammatory IL-4-polarized (M2) macrophages. The initial hypothesis was that Batf2 is a master regulator of gene expression that orchestrates M1 polarization. To investigate a potential role of Batf2 during macrophage polarization, its expression in M1 polarized macrophages was examined. Batf2 mRNA appears within 60 minutes following LPS/ IFNγ treatment and is sustained for at least 48 hours. To address the hypothesis that Batf2 acts as a master transcriptional factor driving a functional M1 phenotype, we have established macrophage cell lines that constitutively express Batf2. Batf2 overexpression did not enhance key M1-associated genes, including iNOS and H2-Aa, but did enhance LPS/IFNγ-driven Cxcl10. Batf2 overexpression also failed to suppress key M2-associated genes including Fizz1 and Mrc1. Batf2 overexpression also failed to alter multiple non-immunity-related genes established or predicted to be downstream of Batf2 in macrophages or other cells. Overall, contrary to our initial hypothesis, constitutive Batf2 expression by itself does not appear to broadly induce M1 gene expression; rather, it appears to enhance only select genes. Since other Batf family members interact with members of the IRF family, I discuss the possibility that Batf2 works in conjunction with a limiting cofactor, possibly Irf family members and/or other regulatory proteins.
Recommended Citation
Gehman, Marie A., "THE ROLE OF BATF2 IN LPS/IFNγ POLARIZED MACROPHAGES" (2015). Theses and Dissertations--Microbiology, Immunology, and Molecular Genetics. 10.
https://uknowledge.uky.edu/microbio_etds/10
