Divergence of bacterial lipopolysaccharide pro-apoptotic signaling downstream of IRAK-1.
The vascular endothelium is a key target of circulating bacterial lipopolysaccharide (LPS). LPS elicits a wide array of endothelial responses, including the up-regulation of cytokines, adhesion molecules, and tissue factor, many of which are dependent on NF-kappa B activation. In addition, LPS has been demonstrated to induce endothelial apoptosis both in vitro and in vivo. Although the mechanism by which LPS activates NF-kappa B has been well elucidated, the signaling pathway(s) involved in LPS-induced apoptosis remains unknown. Using a variety of dominant negative constructs, we have identified a role for MyD88 and interleukin-1 receptor-associated kinase-1 (IRAK-1) in mediating LPS pro-apoptotic signaling in human endothelial cells. We also demonstrate that LPS-induced endothelial NF-kappa B activation and apoptosis occur independent of one another. Together, these data suggest that the proximal signaling molecules involved in LPS-induced NF-kappa B activation have a requisite involvement in LPS-induced apoptosis and that the pathways leading to NF-kappa B activation and apoptosis diverge downstream of IRAK-1.
Bannerman
Douglas D
DD
Department of Surgery, University of Washington School of Medicine, Seattle, Washington 98104, USA. dbannerm@u.washington.edu
Tupper
Joan C
JC
Erwert
Ryan D
RD
Winn
Robert K
RK
Harlan
John M
JM
D048868:Adaptor Proteins, Signal Transducing; D000256:Adenoviridae / Q000378:metabolism; D000943:Antigens, Differentiation / Q000378:metabolism; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007375:Interleukin-1 / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases; D008070:Lipopolysaccharides / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000378:metabolism; D011112:Polymyxin B / Q000494:pharmacology; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014161:Transduction, Genetic
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D018076:DNA, Complementary; D007375:Interleukin-1; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D011971:Receptors, Immunologic; D008156:Luciferases; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases; D020169:Caspases; D011112:Polymyxin B