Dissertation/Thesis Abstract

Cooperative stimulation of endothelium with interferon-γ and Borrelia burgdorferi promotes chronic inflammatory changes
by Dame, Tarah Marie, Ph.D., State University of New York at Stony Brook, 2007, 149; 3299708
Abstract (Summary)

Borrelia burgdorferi, the agent of Lyme disease, promotes pro-inflammatory changes in endothelium that lead to the recruitment of leukocytes. The host immune response to infection results in increased levels of interferon (IFN)-γ in the serum and lesions of Lyme disease patients that correlate with greater severity of disease. Therefore, the effect of IFN-γ on the gene expression profile of primary human umbilical vein endothelial cells (HUVEC) exposed to B. burgdorferi was determined via microarray analysis. B. burgdorferi and IFN-γ synergistically augmented the expression of 34 genes, seven of which encode chemokines. Six of these chemokines (CCL7, CCL8, CX3CL1, CXCL9, CXCLIO, and CXCL11) attract T lymphocytes, and one (CXCL2) is specific for neutrophils. The enhanced transcription of select genes (CXCL10, CXCL11 and CXCL2) was further validated using real-time polymerase chain reaction. Moreover, synergistic production of the chemoattractants for T cells was confirmed at the protein level. The kinetics and specificity of the observed cooperative activation of endothelium by B. burgdorferi and IFN-γ were further examined using CXCLIO as the read-out. B. burgdorferi and IFN-γ acted together to induce secretion of CXCLIO by HUVEC in a time- and concentration-dependent manner. Interleukin-1β, tumor necrosis factor-α, and Escherichia coli lipopolysaccharide also cooperated with IFN-γ to induce synergistic production of CXCL10 by endothelium, indicating that IFN-γ potentiates inflammation in concert with a variety of mediators. Interleukin-10 selectively inhibited the production of CXCL10 by IFN-γ in combination with B. burgdorferi and lipopolysaccharide but not with the host cytokines interlcukin-1β and tumor necrosis factor-α.

The functional consequences of increased production of chemokines by HUVEC stimulated concurrently with B. burgdorferi and IFN-γ were assessed using an in vitro model of the blood vessel wall. An increased number of human T lymphocytes traversed endothelium exposed to B. burgdorferi and IFN-γ, as compared to unstimulated endothelial monolayers. In contrast, addition of IFN-γ diminished the migration of neutrophils across B. burgdorferi-activated endothelium. IFN-γ thus alters gene expression by endothelium exposed to B. burgdorferi in a manner that promotes recruitment of T cells and suppresses that of neutrophils. This modulation may facilitate the development of chronic inflammatory lesions in Lyme disease.

Indexing (document details)
Advisor:
Commitee:
School: State University of New York at Stony Brook
School Location: United States -- New York
Source: DAI-B 69/01, Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Microbiology
Keywords: Borrelia burgdorferi, Chemokines, Endothelium, Inflammatory changes
Publication Number: 3299708
ISBN: 9780549436287
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