Date on Master's Thesis/Doctoral Dissertation

5-2011

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Microbiology and Immunology

Committee Chair

Mitchell, Thomas C.

Author's Keywords

Toll-like receptor 4; Cell signaling; Inflammasome; Inflammation; Lipid A/LPS

Subject

Lipids; Anti-inflammatory agents

Abstract

Monophosphoryl Lipid A (MPLA), a derivative of LPS endotoxin, is a TLR4 agonist that displays as little as 0.1-1% as much toxicity as its parent molecule while retaining immunostimulatory properties. We discovered that MPLA activates a TRIF-biased pattern of TLR4 signaling, resulting in reduced production of MyD88-dependent pro-inflammatory factors, and credited TRIF-bias for MPLA's reduced toxicity. A contemporary study showed that MPLA fails to promote maturation of the potent inflammatory cytokine IL-1ß. This dissertation seeks to reconcile MPLA's TRIF-biased signaling with IL-1 ß loss, and to determine the ultimate cause of MPLA's reduced toxicity compared to LPS. We find that TRIF-biased TLR4 activation results in weak MyD88-dependent induction of NLRP3, a critical inflammasome component required for IL-1 ß production. MPLA's loss of IL-1 ß results in decreased potentiation of MyD88-dependent inflammatory factors in vivo and reduced IL-1 RI-dependent hepatotoxicity. Ultimately, TRIF-biased TLR4 signaling is the causative factor resulting in MPLA's immunogenicity with low toxicity; however more studies are needed to determine the initial events leading to the TRIF-dependent Signaling cascade. This dissertation describes the mechanisms responsible for MPLA's reduced induction of inflammatory responses and outlines how this signaling may be exploited for therapeutic use.

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