Dissertation/Thesis Abstract

Gene-specific control of inflammation by toll-like-receptor induced chromatin modifications
by Foster, Simmie Lorene, Ph.D., Yale University, 2008, 128; 3317263
Abstract (Summary)

Toll-like receptors (TLRs) induce a complex inflammatory response that functions to alert the body to infection, neutralize pathogens, and repair damaged tissues. An excessive or persistent inflammatory response can be fatal, so multiple regulatory mechanisms have evolved to control the extent and duration of inflammation. Our current understanding of the control of inflammation is based on negative regulation of TLR signaling. However, TLR-induced genes have diverse functions, and control of signaling pathways does not allow for groups of genes with distinct functions to be differentially regulated. Therefore we hypothesized that additional, component-specific control mechanisms must exist. Using an in vitro system of lipopolysaccharide tolerance in macrophages, we show that TLR-induced genes fall into two categories on the basis of their functions and regulatory requirements. We demonstrate that representatives from the two classes acquire distinct patterns of TLR-induced chromatin modifications. These gene-specific chromatin modifications are associated with transient silencing of one class of genes, which includes pro-inflammatory mediators, and priming of the second class, which includes antimicrobial effectors. In addition, we show that anti-inflammatory agents such as IL-10 and corticosteroids also differentially regulate TLR-induced genes. These findings illustrate an adaptive response in macrophages, and reveal component-specific regulation of inflammation.

Indexing (document details)
Advisor: Medzhitov, Ruslan
Commitee:
School: Yale University
School Location: United States -- Connecticut
Source: DAI-B 69/06, Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Molecular biology, Microbiology, Immunology
Keywords: Chromatin, Gene regulation, Inflammation, Innate immunity, Toll-like receptors
Publication Number: 3317263
ISBN: 9780549653042
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