Date of Award

7-2010

Degree Type

Thesis

Degree Name

MS Biology

Department

Biology

Advisor

Allan D. Blake

Committee Member

Angela Klaus

Committee Member

Tin-Chun Chu

Committee Member

Carroll Rawn

Committee Member

Carolyn Bentivegna

Keywords

Tumor necrosis factor alpha (TNF-a), Cytokine, Small molecule inhibition, Chronic inflammatory disorders

Abstract

Tumor Necrosis Factor Alpha (TNF-a) is a vital pro-inflammatory cytokine produced in response to the activation ofthe innate immune response via the Toll-like receptor signal transduction pathway. This thesis explores the release and inhibition of TNF-a from RAW 264.7 mouse macrophages and human U937 cells that have been exposed to a potent activator of innate immunity. Using lipopolysaccharide (LPS), a Gram negative bacterial endotoxin, in the presence or absence of proinflammatory cytokine interferon 'Y (IFN-y) as activators ofthe TLR-4 pathway, a robust release ofTNF­ a was observed. Co-incubation of stimulated macrophages with the tyrosine phosphatase inhibitor, sodium vanadate, resulted in a time and concentration dependent inhibition of stimulated TNF-a release. These results demonstrate for the first time that soluble TNF-a release can be inhibited by a small molecule tyrosine phosphatase inhibitor, and indicates that protein tyrosine phosphorylation is critical to macrophage TNF-a release. Since the inappropriate expression of TNF-a occurs in the pathogenesis of many chronic inflammatory disorders, these results provide a potentially novel mechanism for regulating macrophage TNF-a release.

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