期刊
INFECTION AND IMMUNITY
卷 71, 期 8, 页码 4414-4420出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/IAI.71.8.4414-4420.2003
关键词
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资金
- NHLBI NIH HHS [HL72262, P01 HL018645, P01 HL072262, HL18645] Funding Source: Medline
Many of the proinflammatory effects of gram-negative bacteria are elicited by the interaction of bacterial lipopolysaccharide (LPS) with Toll-like receptor 4 (TLR4) expressed on host cells. TLR4 signaling leads to activation of NF-kappaB and transcription of many genes involved in the inflammatory response. In this study, we examined the signaling pathways involved in NF-kappaB activation by TLR4 signaling in human microvascular endothelial cells. Akt is a major downstream target of phosphoinositide 3 kinase (PI3-kinase), and PI3-kinase activation is necessary and sufficient for Akt phosphorylation. Consequently, Akt kinase activation was used as a measure of PI3-kinase activity. In a stable transfection system, dominant-negative mutants of myeloid differentiation factor 88 (MyD88) and interleukin-1 (IL-1) receptor-associated kinase 1 (IRAK-1) (MyD88-TIR and IRAK-DD, respectively) blocked Akt kinase activity in response to LPS and IL-1beta. A dominant-negative mutant (Mal-P/H) of MyD88 adapter-like protein (Mal), a protein with homology to MyD88, failed to inhibit LPS- or IL-1beta-induced Akt activity. Moreover, a dominant-negative mutant of p85 (p85-DN) inhibited the NF-kappaB luciferase activity, IL-6 production, and IkappaBalpha degradation elicited by LPS and IL-1beta but not that stimulated by tumor necrosis factor alpha. The dominant-negative mutant of Akt partially inhibited the NF-kappaB luciferase activity evoked by LPS and IL-1beta. However, expression of a constitutively activated Akt failed to induce NF-kappaB luciferase activity. These findings indicate that TLR4- and IL-1R-induced PI3-kinase activity is mediated by the adapter proteins MyD88 and IRAK-I but not Mal. Further, these studies suggest that PI3-kinase is an important mediator of LPS and IL-1beta signaling leading to NF-kappaB activation in endothelial cells and that Akt is necessary but not sufficient for NF-kappaB activation by TLR4.
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