


* The Pulmonary Center, Boston University School of Medicine, Boston Massachusetts, and
Mycobacteria Research Laboratories, Department of Microbiology, Colorado State University, Ft. Collins, Colorado
Correspondence: Dr. Matthew J. Fenton, Pulmonary Center R-220, Boston University School of Medicine, 80 East Concord St., Boston MA 02118-2394. E-mail: mfenton{at}bu.edu
We previously reported that gram-negative bacterial lipopolysaccharide
(LPS) activates cells via Toll-like receptor (TLR) 4, whereas the
mycobacterial cell wall glycolipid lipoarabinomannan (LAM) activates
cells via TLR2. We also identified a secreted TLR2 agonist activity in
short-term culture filtrates of Mycobacterium tuberculosis
bacilli, termed soluble tuberculosis factor (STF). Here we show that
STF contains mannosylated phosphatidylinositol (PIM) and that purified
PIM possesses TLR2 agonist activity. Stimulation of RAW 264.7
macrophages by LPS, LAM, STF, and PIM rapidly activated nuclear factor
(NF)-
B, activator protein-1 (AP-1), and mitogen-activated protein
(MAP) kinases. These TLR agonists induced similar levels of NF-
B and
AP-1 DNA-binding activity, as well as trans-activation
function. Unexpectedly, these TLR agonists induced tumor necrosis
factor
secretion, whereas only LPS was capable of inducing
interleukin-1ß and nitric oxide secretion. Thus, different TLR
proteins are still capable of activating distinct cellular responses,
in spite of their shared capacities to activate NF-
B, AP-1, and MAP
kinases.
Key Words: signal transduction tuberculosis innate immunity
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G. Melmed, L. S. Thomas, N. Lee, S. Y. Tesfay, K. Lukasek, K. S. Michelsen, Y. Zhou, B. Hu, M. Arditi, and M. T. Abreu Human Intestinal Epithelial Cells Are Broadly Unresponsive to Toll-Like Receptor 2-Dependent Bacterial Ligands: Implications for Host-Microbial Interactions in the Gut J. Immunol., February 1, 2003; 170(3): 1406 - 1415. [Abstract] [Full Text] [PDF] |
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M. A. Dobrovolskaia, A. E. Medvedev, K. E. Thomas, N. Cuesta, V. Toshchakov, T. Ren, M. J. Cody, S. M. Michalek, N. R. Rice, and S. N. Vogel Induction of In Vitro Reprogramming by Toll-Like Receptor (TLR)2 and TLR4 Agonists in Murine Macrophages: Effects of TLR "Homotolerance" Versus "Heterotolerance" on NF-{kappa}B Signaling Pathway Components J. Immunol., January 1, 2003; 170(1): 508 - 519. [Abstract] [Full Text] [PDF] |
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E. K. Brint, K. A. Fitzgerald, P. Smith, A. J. Coyle, J.-C. Gutierrez-Ramos, P. G. Fallon, and L. A. J. O'Neill Characterization of Signaling Pathways Activated by the Interleukin 1 (IL-1) Receptor Homologue T1/ST2. A ROLE FOR JUN N-TERMINAL KINASE IN IL-4 INDUCTION J. Biol. Chem., December 13, 2002; 277(51): 49205 - 49211. [Abstract] [Full Text] [PDF] |
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D. Schilling, K. Thomas, K. Nixdorff, S. N. Vogel, and M. J. Fenton Toll-Like Receptor 4 and Toll-IL-1 Receptor Domain-Containing Adapter Protein (TIRAP)/Myeloid Differentiation Protein 88 Adapter-Like (Mal) Contribute to Maximal IL-6 Expression in Macrophages J. Immunol., November 15, 2002; 169(10): 5874 - 5880. [Abstract] [Full Text] [PDF] |
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M. R. Horton, S. Boodoo, and J. D. Powell NF-kappa B Activation Mediates the Cross-talk between Extracellular Matrix and Interferon-gamma (IFN-gamma ) Leading to Enhanced Monokine Induced by IFN-gamma (MIG) Expression in Macrophages J. Biol. Chem., November 8, 2002; 277(46): 43757 - 43762. [Abstract] [Full Text] [PDF] |
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A. E. Medvedev, A. Lentschat, L. M. Wahl, D. T. Golenbock, and S. N. Vogel Dysregulation of LPS-Induced Toll-Like Receptor 4-MyD88 Complex Formation and IL-1 Receptor-Associated Kinase 1 Activation in Endotoxin-Tolerant Cells J. Immunol., November 1, 2002; 169(9): 5209 - 5216. [Abstract] [Full Text] [PDF] |
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A. D. Edwards, S. P. Manickasingham, R. Sporri, S. S. Diebold, O. Schulz, A. Sher, T. Kaisho, S. Akira, and C. Reis e Sousa Microbial Recognition Via Toll-Like Receptor-Dependent and -Independent Pathways Determines the Cytokine Response of Murine Dendritic Cell Subsets to CD40 Triggering J. Immunol., October 1, 2002; 169(7): 3652 - 3660. [Abstract] [Full Text] [PDF] |
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B. Abel, N. Thieblemont, V. J. F. Quesniaux, N. Brown, J. Mpagi, K. Miyake, F. Bihl, and B. Ryffel Toll-Like Receptor 4 Expression Is Required to Control Chronic Mycobacterium tuberculosis Infection in Mice J. Immunol., September 15, 2002; 169(6): 3155 - 3162. [Abstract] [Full Text] [PDF] |
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A. Blumenthal, S. Ehlers, M. Ernst, H.-D. Flad, and N. Reiling Control of Mycobacterial Replication in Human Macrophages: Roles of Extracellular Signal-Regulated Kinases 1 and 2 and p38 Mitogen-Activated Protein Kinase Pathways Infect. Immun., September 1, 2002; 70(9): 4961 - 4967. [Abstract] [Full Text] [PDF] |
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S. E. Applequist, R. P. A. Wallin, and H.-G. Ljunggren Variable expression of Toll-like receptor in murine innate and adaptive immune cell lines Int. Immunol., September 1, 2002; 14(9): 1065 - 1074. [Abstract] [Full Text] [PDF] |
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M. Guha and N. Mackman The Phosphatidylinositol 3-Kinase-Akt Pathway Limits Lipopolysaccharide Activation of Signaling Pathways and Expression of Inflammatory Mediators in Human Monocytic Cells J. Biol. Chem., August 23, 2002; 277(35): 32124 - 32132. [Abstract] [Full Text] [PDF] |
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T. Wang, W. P. Lafuse, K. Takeda, S. Akira, and B. S. Zwilling Rapid Chromatin Remodeling of Toll-Like Receptor 2 Promoter During Infection of Macrophages with Mycobacterium avium J. Immunol., July 15, 2002; 169(2): 795 - 801. [Abstract] [Full Text] [PDF] |
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V. Haehnel, L. Schwarzfischer, M. J. Fenton, and M. Rehli Transcriptional Regulation of the Human Toll-Like Receptor 2 Gene in Monocytes and Macrophages J. Immunol., June 1, 2002; 168(11): 5629 - 5637. [Abstract] [Full Text] [PDF] |
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V. S. Carl, K. Brown-Steinke, M. J. H. Nicklin, and M. F. Smith Jr. Toll-like Receptor 2 and 4 (TLR2 and TLR4) Agonists Differentially Regulate Secretory Interleukin-1 Receptor Antagonist Gene Expression in Macrophages J. Biol. Chem., May 10, 2002; 277(20): 17448 - 17456. [Abstract] [Full Text] [PDF] |
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B. G. Yipp, G. Andonegui, C. J. Howlett, S. M. Robbins, T. Hartung, M. Ho, and P. Kubes Profound Differences in Leukocyte-Endothelial Cell Responses to Lipopolysaccharide Versus Lipoteichoic Acid J. Immunol., May 1, 2002; 168(9): 4650 - 4658. [Abstract] [Full Text] [PDF] |
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M. Martin, J. Katz, S. N. Vogel, and S. M. Michalek Differential Induction of Endotoxin Tolerance by Lipopolysaccharides Derived from Porphyromonas gingivalis and Escherichia coli J. Immunol., November 1, 2001; 167(9): 5278 - 5285. [Abstract] [Full Text] [PDF] |
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B W Jones, K A Heldwein, T K Means, J J Saukkonen, and M J Fenton Differential roles of Toll-like receptors in the elicitation of proinflammatory responses by macrophages Ann Rheum Dis, November 1, 2001; 60(90003): iii6 - 12. [Abstract] [Full Text] [PDF] |
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E. Trogan, R. P. Choudhury, H. M. Dansky, J. X. Rong, J. L. Breslow, and E. A. Fisher Laser capture microdissection analysis of gene expression in macrophages from atherosclerotic lesions of apolipoprotein E-deficient mice PNAS, February 19, 2002; 99(4): 2234 - 2239. [Abstract] [Full Text] [PDF] |
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