This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Li, X.
Right arrow Articles by Harlan, J. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Li, X.
Right arrow Articles by Harlan, J. M.

 Previous Article  |  Next Article 

Infection and Immunity, August 2003, p. 4414-4420, Vol. 71, No. 8
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.8.4414-4420.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Phosphoinositide 3 Kinase Mediates Toll-Like Receptor 4-Induced Activation of NF-{kappa}B in Endothelial Cells

Xianwu Li,1 Joan C. Tupper,1 Douglas D. Bannerman,2 Robert K. Winn,3 Christopher J. Rhodes,4,5 and John M. Harlan1*

Departments of Medicine,1 Surgery,3 Pharmacology, University of Washington, Seattle, Washington 98195,4 Immunology and Disease Resistance Laboratory, USDA-Agricultural Research Service, Beltsville, Maryland 20705,2 Pacific Northwest Research Institute, Seattle, Washington 981225

Received 30 December 2002/ Returned for modification 7 February 2003/ Accepted 16 May 2003

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-{kappa}B and transcription of many genes involved in the inflammatory response. In this study, we examined the signaling pathways involved in NF-{kappa}B 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-1ß. 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-1ß-induced Akt activity. Moreover, a dominant-negative mutant of p85 (p85-DN) inhibited the NF-{kappa}B luciferase activity, IL-6 production, and I{kappa}B{alpha} degradation elicited by LPS and IL-1ß but not that stimulated by tumor necrosis factor alpha. The dominant-negative mutant of Akt partially inhibited the NF-{kappa}B luciferase activity evoked by LPS and IL-1ß. However, expression of a constitutively activated Akt failed to induce NF-{kappa}B luciferase activity. These findings indicate that TLR4- and IL-1R-induced PI3-kinase activity is mediated by the adapter proteins MyD88 and IRAK-1 but not Mal. Further, these studies suggest that PI3-kinase is an important mediator of LPS and IL-1ß signaling leading to NF-{kappa}B activation in endothelial cells and that Akt is necessary but not sufficient for NF-{kappa}B activation by TLR4.

* Corresponding author. Mailing address: Division of Hematology, University of Washington, Harborview Medical Center, Box 359756, Seattle, WA 98104-2499. Phone: (206) 341-5314. Fax: (206) 341-5312. E-mail: jharlan{at}u.washington.edu.

Editor: J. T. Barbieri

Infection and Immunity, August 2003, p. 4414-4420, Vol. 71, No. 8
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.8.4414-4420.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Chandras, C., Koutmani, Y., Kokkotou, E., Pothoulakis, C., Karalis, K. P. (2009). Activation of Phosphatidylinositol 3-Kinase/Protein Kinase B by Corticotropin-Releasing Factor in Human Monocytes. Endocrinology 150: 4606-4614 [Abstract] [Full Text]  
  • Good, D. W., George, T., Watts, B. A. III (2009). Lipopolysaccharide directly alters renal tubule transport through distinct TLR4-dependent pathways in basolateral and apical membranes. Am. J. Physiol. Renal Physiol. 297: F866-F874 [Abstract] [Full Text]  
  • Laird, M. H. W., Rhee, S. H., Perkins, D. J., Medvedev, A. E., Piao, W., Fenton, M. J., Vogel, S. N. (2009). TLR4/MyD88/PI3K interactions regulate TLR4 signaling. J. Leukoc. Biol. 85: 966-977 [Abstract] [Full Text]  
  • Liu, J., Wang, S., Zhang, P., Said-Al-Naief, N., Michalek, S. M., Feng, X. (2009). Molecular Mechanism of the Bifunctional Role of Lipopolysaccharide in Osteoclastogenesis. J. Biol. Chem. 284: 12512-12523 [Abstract] [Full Text]  
  • Walton, K. L. W., Holt, L., Sartor, R. B. (2009). Lipopolysaccharide activates innate immune responses in murine intestinal myofibroblasts through multiple signaling pathways. Am. J. Physiol. Gastrointest. Liver Physiol. 296: G601-G611 [Abstract] [Full Text]  
  • Tiruppathi, C., Shimizu, J., Miyawaki-Shimizu, K., Vogel, S. M., Bair, A. M., Minshall, R. D., Predescu, D., Malik, A. B. (2008). Role of NF-{kappa}B-dependent Caveolin-1 Expression in the Mechanism of Increased Endothelial Permeability Induced by Lipopolysaccharide. J. Biol. Chem. 283: 4210-4218 [Abstract] [Full Text]  
  • Ghose, R., White, D., Guo, T., Vallejo, J., Karpen, S. J. (2008). Regulation of Hepatic Drug-Metabolizing Enzyme Genes by Toll-Like Receptor 4 Signaling Is Independent of Toll-Interleukin 1 Receptor Domain-Containing Adaptor Protein. Drug Metab. Dispos. 36: 95-101 [Abstract] [Full Text]  
  • Shao, H., Shen, Y., Liu, H., Dong, G., Qiang, J., Jing, H. (2007). Simvastatin Suppresses Lung Inflammatory Response in a Rat Cardiopulmonary Bypass Model. Ann. Thorac. Surg. 84: 2011-2018 [Abstract] [Full Text]  
  • Bafica, A., Feng, C. G., Santiago, H. C., Aliberti, J., Cheever, A., Thomas, K. E., Taylor, G. A., Vogel, S. N., Sher, A. (2007). The IFN-Inducible GTPase LRG47 (Irgm1) Negatively Regulates TLR4-Triggered Proinflammatory Cytokine Production and Prevents Endotoxemia. J. Immunol. 179: 5514-5522 [Abstract] [Full Text]  
  • Goldberg, A., Parolini, M., Chin, B. Y., Czismadia, E., Otterbein, L. E., Bach, F. H., Wang, H. (2007). Toll-like receptor 4 suppression leads to islet allograft survival. FASEB J. 21: 2840-2848 [Abstract] [Full Text]  
  • Gobert, A. P., Vareille, M., Glasser, A.-L., Hindre, T., de Sablet, T., Martin, C. (2007). Shiga Toxin Produced by Enterohemorrhagic Escherichia coli Inhibits PI3K/NF-{kappa}B Signaling Pathway in Globotriaosylceramide-3-Negative Human Intestinal Epithelial Cells. J. Immunol. 178: 8168-8174 [Abstract] [Full Text]  
  • Kim, F., Pham, M., Luttrell, I., Bannerman, D. D., Tupper, J., Thaler, J., Hawn, T. R., Raines, E. W., Schwartz, M. W. (2007). Toll-Like Receptor-4 Mediates Vascular Inflammation and Insulin Resistance in Diet-Induced Obesity. Circ. Res. 100: 1589-1596 [Abstract] [Full Text]  
  • Lee, J. S., Nauseef, W. M., Moeenrezakhanlou, A., Sly, L. M., Noubir, S., Leidal, K. G., Schlomann, J. M., Krystal, G., Reiner, N. E. (2007). Monocyte p110{alpha} phosphatidylinositol 3-kinase regulates phagocytosis, the phagocyte oxidase, and cytokine production. J. Leukoc. Biol. 81: 1548-1561 [Abstract] [Full Text]  
  • Hasan, U. A., Caux, C., Perrot, I., Doffin, A.-C., Menetrier-Caux, C., Trinchieri, G., Tommasino, M., Vlach, J. (2007). Cell proliferation and survival induced by Toll-like receptors is antagonized by type I IFNs. Proc. Natl. Acad. Sci. USA 104: 8047-8052 [Abstract] [Full Text]  
  • Mahieu, T., Libert, C. (2007). Should We Inhibit Type I Interferons in Sepsis?. Infect. Immun. 75: 22-29 [Full Text]  
  • Qi, H.-Y., Shelhamer, J. H. (2005). Toll-like Receptor 4 Signaling Regulates Cytosolic Phospholipase A2 Activation and Lipid Generation in Lipopolysaccharide-stimulated Macrophages. J. Biol. Chem. 280: 38969-38975 [Abstract] [Full Text]  
  • Wu, S.-Q., Aird, W. C. (2005). Thrombin, TNF-{alpha}, and LPS exert overlapping but nonidentical effects on gene expression in endothelial cells and vascular smooth muscle cells. Am. J. Physiol. Heart Circ. Physiol. 289: H873-H885 [Abstract] [Full Text]  
  • Francois, S., El Benna, J., Dang, P. M. C., Pedruzzi, E., Gougerot-Pocidalo, M.-A., Elbim, C. (2005). Inhibition of Neutrophil Apoptosis by TLR Agonists in Whole Blood: Involvement of the Phosphoinositide 3-Kinase/Akt and NF-{kappa}B Signaling Pathways, Leading to Increased Levels of Mcl-1, A1, and Phosphorylated Bad. J. Immunol. 174: 3633-3642 [Abstract] [Full Text]  
  • Manna, S. K., Ramesh, G. T. (2005). Interleukin-8 Induces Nuclear Transcription Factor-{kappa}B through a TRAF6-dependent Pathway. J. Biol. Chem. 280: 7010-7021 [Abstract] [Full Text]  
  • Bannerman, D. D., Eiting, K. T., Winn, R. K., Harlan, J. M. (2004). FLICE-Like Inhibitory Protein (FLIP) Protects Against Apoptosis and Suppresses NF-{kappa}B Activation Induced by Bacterial Lipopolysaccharide. Am. J. Pathol. 165: 1423-1431 [Abstract] [Full Text]  
  • Schabbauer, G., Tencati, M., Pedersen, B., Pawlinski, R., Mackman, N. (2004). PI3K-Akt Pathway Suppresses Coagulation and Inflammation in Endotoxemic Mice. Arterioscler. Thromb. Vasc. Bio. 24: 1963-1969 [Abstract] [Full Text]  
  • Sahni, A., Guo, M., Sahni, S. K., Francis, C. W. (2004). Interleukin-1{beta} but not IL-1{alpha} binds to fibrinogen and fibrin and has enhanced activity in the bound form. Blood 104: 409-414 [Abstract] [Full Text]  
  • Noubir, S., Hmama, Z., Reiner, N. E. (2004). Dual Receptors and Distinct Pathways Mediate Interleukin-1 Receptor-associated Kinase Degradation in Response to Lipopolysaccharide: INVOLVEMENT OF CD14/TLR4, CR3, AND PHOSPHATIDYLINOSITOL 3-KINASE. J. Biol. Chem. 279: 25189-25195 [Abstract] [Full Text]  
  • Strassheim, D., Asehnoune, K., Park, J.-S., Kim, J.-Y., He, Q., Richter, D., Kuhn, K., Mitra, S., Abraham, E. (2004). Phosphoinositide 3-Kinase and Akt Occupy Central Roles in Inflammatory Responses of Toll-Like Receptor 2-Stimulated Neutrophils. J. Immunol. 172: 5727-5733 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»