抄録
Apolipoprotein E (apoE) affects immune responses and suppresses inflammation in an isoform specific manner. COG133 is a peptide corresponding to residues 133-149 of holo-apoE that possesses the immunomodulatory properties of holo-apoE. In response to lipopolysaccharide (LPS), COG133 significantly down-regulates the release of nitric oxide (NO), IL-6 and TNFa in BV2 microglial cells and in C57Bl/6 mice. These results suggested that we could employ the apoE-peptide, COG133, as a tool to understand how apoE suppresses inflammatory responses. LPS binding to Toll-Like Receptor-4 (TLR4) activates an intracellular signal transduction cascade, which includes phosphorylation of MAP kinases and transcription factors, that eventually participate in stimulating NO and TNFa release. LPS induced phosphorylation of IkB and levels of phospho-IkB were reduced in the presence of COG133. Phosphorylation of IkB is needed to activate NFkB DNA-binding activity and COG133 reduced phospho-IkB levels resulting in decreased NFkB DNA-binding activity. LPS also induced the levels of phosphorylated p38-MAP kinase, ERK and JNK, but the levels of these phospho-proteins were significantly reduced in the presence of COG133 suggesting another site of apoE-peptide action on this inflammatory signaling cascade. apoE peptides corresponding to COG133 were found to bind to cell-surface receptors that bind holo-apoE. We examined the role of these receptors in COG133 function. Independent of the presence or absence of LDL receptors, LPS plus COG133 treated macrophages released significantly less NO than their LPS treated counterparts. [J Physiol Sci. 2008;58 Suppl:S151]
