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作者 Jacinto, Randolph Bambao
書名 Innate immunity adaptation and sensitization by toll-like receptor (TLR)2-, TLR4- and TLR9-specific microbial pathogens in human monocytic cells
國際標準書號 0496709843
book jacket
說明 169 p
附註 Source: Dissertation Abstracts International, Volume: 65-02, Section: B, page: 0644
Advisers: Charles E. McCall; Liwu Li
Thesis (Ph.D.)--Wake Forest University, The Bowman Gray School of Medicine, 2004
Sepsis with endotoxic shock is the number one cause of death in critical care units in the Unites States. During infection from gram-negative bacteria, lipopolysaccharide (LPS) induces proinflammatory gene expression. Subsequent exposure to LPS, a TLR4 specific microbial agonist, induces a gene specific adaptive cellular response called endotoxin tolerance, a phenomenon common to sepsis whereby expression of proinflammatory mediators are repressed. In light of the growing number of septic cases being attributed to other microbial pathogens, questions regarding the potential of other microbial pathogens to induce similar states of innate immunity adaptation have been raised. This thesis will demonstrate prior exposure to lipoteichoic acid (LTA), a TLR2 specific microbial agonist, induces only homotolerance, a phenomenon whereby repressed innate immune response results from restimulation with the same microbial agonist. Additionally, this thesis will demonstrate that TLR4 can engage in cross-talk with TLR2 and TLR9, inducing both homo- and heterotolerance, a phenomenon whereby repression of the innate immunity results from restimulation with a different microbial agonist
Dissimilar to the adapted phenotype, the innate immunity also exhibits a sensitized phenotype whereby subsequent exposure to LPS enhances proinflammatory gene expression. This thesis will demonstrate that, in contrast to TLR4 and TLR2, CpG ODN, a TLR9 specific microbial agonist induces both states of homo- and heterosensitization to CpG ODN and LPS restimulation, respectively
To determine the molecular mechanisms responsible for the differential expression of innate immunity adaptation and sensitization, investigations into the regulation of interleukin-1 receptor-associated kinase-1 (IRAK-1) were made using the THP-1 cell lines as a model for sepsis. Kinase inactivation and protein degradation of IRAK-1 corresponds with LPS homo- and heterotolerance while only kinase inactivation corresponds with LTA homotolerance. With respect to the primed phenotype, IRAK-1 remains responsive in CpG ODN heterosenitization while no kinase activation and degradation were observed in CpG ODN homosensitization. Therefore, distinct alterations in IRAK-1 play a role, at least in part to the induction of innate immunity adaptation and sensitization
School code: 0249
Host Item Dissertation Abstracts International 65-02B
主題 Health Sciences, Immunology
Health Sciences, Medicine and Surgery
Biology, Cell
Alt Author Wake Forest University, The Bowman Gray School of Medicine
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