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Degree

Master of Science in Biomedical Sciences (MSBS), University of Toledo Health Science Campus, College of Graduate Studies, 2006.

Abstract

Tumor necrosis factor alpha (TNF-alpha) is a protein that can be produced in large amounts by tissue macrophages and monocytes in response to bacterial products. Systemic release of TNF-alpha has been shown to mediate severe septic shock. Fever, hypotension, cardiovascular changes, disseminated intravascular coagulation (DIC), multiple organ failure and death are characteristics of this disease state. Our study has indicated that the bacterial products, lipopolysaccharide (LPS) and formylated peptides (fMLP), each induce activation of cytokine gene transcription in leukocytes. Interestingly, fMLP induces some intracellular signaling events that differ from those elicited by LPS. Both stimuli, however, activate the signaling pathways that converge to produce TNF-alpha. We have found that the bacterial products, fMLP and LPS, can act synergistically in the induction of TNF-alpha mRNA in monocytes, but is not seen in TNF-alpha protein levels. Our results demonstrate that multiple bacterial products may regulate the production of pro-inflammatory cytokines in a synergistic manner. Control of this inflammation is best understood at the level of synergistic regulation of intracellular signaling. Our results have also exposed a novel and potentially important pathogenic mechanism occurring during bacterial infection. Thus, our overall hypotheses are that leukocyte activation is regulated by multiple bacterial products that operate synergistically by activating multiple signaling pathways,and that this synergy is likely to play a significant role in the induction of host defense to bacterial infections and in the pathogenesis of inflammatory disorders.

Keywords

CMLP; TLR4; Sepsis; TNF-alpha

Advisor

Z. Kevin Pan, Ph.D

Pages

95p.

Document number: mco1164046331
Permalink: http://rave.ohiolink.edu/etdc/view?acc_num=mco1164046331

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