Free full text at:
J Biol Chem. 2003 Sep 24
Lynch JR, Tang W, Wang H, Vitek MP, Bennett ER, Sullivan PM, Warner DS, Laskowitz DT.
Neurology, Duke University Medical Center, Durham, NC 27710.
Human apolipoprotein E is the major apolipoprotein expressed in the brain and exists as three isoforms, designated E2, E3, and E4.
Although evidence suggests that apolipoprotein E plays an important role in modifying systemic and brain inflammatory responses, there is little data investigating apoE isoform-specific effects in vivo.
In this study, we compared the inflammatory responses of targeted-replacement mice expressing the human apoE3 and apoE4 genes following intravenous administration of lipopolysaccharide.
Animals expressing the E4 allele had significantly greater systemic and brain elevations of the pro-inflammatory cytokines TNF and IL-6 as compared to their E3 counterparts, suggesting an isoform-specific effect of the immunomodulatory properties of apoE.
Furthermore, intravenous administration of a small apoE-mimetic peptide derived from the receptor-binding region of the apoE holoprotein (apoE133-149) similarly suppressed both systemic and brain inflammatory responses in mice following lipopolysaccharide administration.
These results suggest that apoE plays an isoform-specific role in mediating the systemic and brain inflammatory responses.
Moreover, since exogenous administration of this apoE mimetic peptide is effective at suppressing both systemic and brain inflammation, it may represent a novel therapeutic strategy for diseases characterized by systemic or CNS inflammation, such as septic shock, multiple sclerosis, and traumatic brain injury.