Thesis (D.Sc.)--Boston University, Henry M. Goldman School of Dental Medicine, 2004 (Oral Biology). / Includes bibliography (leaves 107-151). / Lipopolysaccharide (LPS), a glycolipid found in the outer membrane of Gram negative
bacteria, induces the secretion of pro-inflammatory cytokines such as tumor necrosis
factor alpha (TNF-a) and interleukin (IL )-1, by monocytes/macrophages. Excessive and
uncontrolled secretion of these compounds leads to multiple pathological conditions,
such as septic shock. LPS receptors have been shown to be CD14, TLR4 and MD-2. LPS
interaction with these receptors mediates many monocyte/macrophage functions. Even
though only CD14 was demonstrated to bind to LPS, and TLR4/MD-2 were capable of
transducing signals, data only show that LPS and CD 14 were in close proximity to TLR4
and no direct binding was reported. Quite recently, moesin, a member of the ERM
family of proteins, has been also found to function as a receptor for LPS. We have
shown that anti-moesin antibody inhibited the release of TNFa by LPS stimulated
monocytes. Moesin was also found to be necessary for the detection of LPS, where
homozygous knockout mice exhibited 3-fold reduction in neutrophil infiltrates in LPS
injected sites when compared to their wild type controls. When moesin gene expression
was completely suppressed with antisense oligonucleotides, there was a significant
reduction of LPS-induced TNF-a secretion. LPS stimulation of mononuclear phagocytes
activates several intracellular signaling pathways including the phosphorylation of IKBa,
mitogen-activated protein kinase (MAPK) pathways: extracellular signal-regulated
kinases (ERK) 1 / 2 (P44/42), p38. These signaling pathways in tum activate a variety of
transcription factors including NF-KB, which coordinates the induction of several genes
encoding inflammatory mediators. [TRUNCATED]
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/31303 |
| Date | January 2004 |
| Creators | Zawawi, Khalid Hashim |
| Publisher | Boston University |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
| Rights | This work is being made available in OpenBU by permission of its author, and is available for research purposes only. All rights are reserved to the author. |
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