Date of Award

Fall 12-1-2019

Degree Type

Thesis

Degree Name

DScD (Doctor of Science in Dentistry)

Primary Advisor

Dr. Dana Graves

Abstract

The function of the adaptor molecule MyD88 is thought to be independent of toll-like receptor 3 (TLR3) signaling. This study aimed to identify certain previously unknown roles of MyD88 in TLR3 signaling during the promotion of pro-inflammatory cytokine production. Upon conducting an analysis of all the TLR ligands, it was found that the TLR3-specific ligand polyinosinic: polycytidylic acid (Poly I:C) significantly induced the production of TNF proteins and up-regulation of other TLR transcripts, particularly TLR2. Accordingly, TLR3 stimulation also led to a significant up-regulation of the endogenous TLR2 ligands HMGB1 and Hsp60. In contrast, TLR3 silencing significantly down-regulated MyD88 and TLR2 expression, and pro-inflammatory IL-1β, TNF, and IL-8 cytokine secretion. The silencing of MyD88 similarly led to the down-regulation of TLR2, IL1β, TNF, and IL-8, which suggests that MyD88 was active downstream of TLR3. The animal model, i.e., the MyD88 knockout mouse presented with lower TNF, NF-κB , and IRF-3 levels, as compared to those in the control wild type mouse treated with Poly I:C. Taken together, our results demonstrate a previously unknown role of MyD88 in the TLR3 signaling pathway; this finding highlights the importance of TLRs and adapter protein interplay for the modulation of the endogenous TLR ligands involved in pro-inflammatory cytokine regulation.

Included in

Dentistry Commons

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