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*
Pulmonary Center, Boston University School of Medicine, and
Laboratory for Infectious Diseases, Boston Medical Center, Boston, MA 02118; and
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814
We previously showed that viable Mycobacterium
tuberculosis (Mtb) bacilli contain distinct ligands that
activate cells via the mammalian Toll-like receptor (TLR) proteins TLR2
and TLR4. We now demonstrate that expression of a dominant negative
TLR2 or TLR4 proteins in RAW 264.7 macrophages partially blocked
Mtb-induced NF-
B activation. Coexpression of both
dominant negative proteins blocked virtually all Mtb-induced NF-B
activation. The role of the TLR4 coreceptor MD-2 was also examined.
Unlike LPS, Mtb-induced macrophage activation was not augmented by
overexpression of ectopic MD-2. Moreover, cells expressing an
LPS-unresponsive MD-2 mutant responded normally to Mtb. We also
observed that the lipid A-like antagonist E5531 specifically inhibited
TLR4-dependent Mtb-induced cellular responses. E5531 could
substantially block LPS- and Mtb-induced TNF-
production in both RAW
264.7 cells and primary human alveolar macrophages (AM
). E5531
inhibited Mtb-induced AM apoptosis in vitro, an effect that was a
consequence of the inhibition of TNF- production by E5531. In
contrast, E5531 did not inhibit Mtb-induced NO production in RAW 264.7
cells and AM. Mtb-stimulated peritoneal macrophages from TLR2- and
TLR4-deficient animals produced similar amounts of NO compared with
control animals, demonstrating that these TLR proteins are not required
for Mtb-induced NO production. Lastly, we demonstrated that a dominant
negative MyD88 mutant could block Mtb-induced activation of the TNF-
promoter, but not the inducible NO synthase promoter, in murine
macrophages. Together, these data suggest that Mtb-induced TNF-
production is largely dependent on TLR signaling. In contrast,
Mtb-induced NO production may be either TLR independent or mediated by
TLR proteins in a MyD88-independent manner.
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J. Uehori, M. Matsumoto, S. Tsuji, T. Akazawa, O. Takeuchi, S. Akira, T. Kawata, I. Azuma, K. Toyoshima, and T. Seya Simultaneous Blocking of Human Toll-Like Receptors 2 and 4 Suppresses Myeloid Dendritic Cell Activation Induced by Mycobacterium bovis Bacillus Calmette-Guerin Peptidoglycan Infect. Immun., August 1, 2003; 71(8): 4238 - 4249. [Abstract] [Full Text] [PDF]
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C. Ropert, M. Closel, A. C. L. Chaves, and R. T. Gazzinelli Inhibition of a p38/Stress-Activated Protein Kinase-2-Dependent Phosphatase Restores Function of IL-1 Receptor-Associated Kinase-1 and Reverses Toll-Like Receptor 2- and 4-Dependent Tolerance of Macrophages J. Immunol., August 1, 2003; 171(3): 1456 - 1465. [Abstract] [Full Text] [PDF]
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A. B. Kamath, J. Alt, H. Debbabi, and S. M. Behar Toll-Like Receptor 4-Defective C3H/HeJ Mice Are Not More Susceptible than Other C3H Substrains to Infection with Mycobacterium tuberculosis Infect. Immun., July 1, 2003; 71(7): 4112 - 4118. [Abstract] [Full Text] [PDF]
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 G. Fenhalls, G. R. Squires, L. Stevens-Muller, J. Bezuidenhout, G. Amphlett, K. Duncan, and P. T. Lukey Associations between Toll-Like Receptors and Interleukin-4 in the Lungs of Patients with Tuberculosis Am. J. Respir. Cell Mol. Biol., July 1, 2003; 29(1): 28 - 38. [Abstract] [Full Text] [PDF]
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M. C. J. Royle, S. Totemeyer, L. C. Alldridge, D. J. Maskell, and C. E. Bryant Stimulation of Toll-Like Receptor 4 by Lipopolysaccharide During Cellular Invasion by Live Salmonella typhimurium Is a Critical But Not Exclusive Event Leading to Macrophage Responses J. Immunol., June 1, 2003; 170(11): 5445 - 5454. [Abstract] [Full Text] [PDF]
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M. Lopez, L. M. Sly, Y. Luu, D. Young, H. Cooper, and N. E. Reiner The 19-kDa Mycobacterium tuberculosis Protein Induces Macrophage Apoptosis Through Toll-Like Receptor-2 J. Immunol., March 1, 2003; 170(5): 2409 - 2416. [Abstract] [Full Text] [PDF]
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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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S. Becker, M. J. Fenton, and J. M. Soukup Involvement of Microbial Components and Toll-like Receptors 2 And 4 in Cytokine Responses to Air Pollution Particles Am. J. Respir. Cell Mol. Biol., November 1, 2002; 27(5): 611 - 618. [Abstract] [Full Text] [PDF]
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N. Reiling, C. Holscher, A. Fehrenbach, S. Kroger, C. J. Kirschning, S. Goyert, and S. Ehlers Cutting Edge: Toll-Like Receptor (TLR)2- and TLR4-Mediated Pathogen Recognition in Resistance to Airborne Infection with Mycobacterium tuberculosis J. Immunol., October 1, 2002; 169(7): 3480 - 3484. [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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K. Bieback, E. Lien, I. M. Klagge, E. Avota, J. Schneider-Schaulies, W. P. Duprex, H. Wagner, C. J. Kirschning, V. ter Meulen, and S. Schneider-Schaulies Hemagglutinin Protein of Wild-Type Measles Virus Activates Toll-Like Receptor 2 Signaling J. Virol., July 29, 2002; 76(17): 8729 - 8736. [Abstract] [Full Text] [PDF]
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M.M. Monick and G.W. Hunninghake Activation of second messenger pathways in alveolar macrophages by endotoxin Eur. Respir. J., July 1, 2002; 20(1): 210 - 222. [Abstract] [Full Text] [PDF]
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J. Hellman, J. D. Roberts Jr., M. M. Tehan, J. E. Allaire, and H. S. Warren Bacterial Peptidoglycan-associated Lipoprotein Is Released into the Bloodstream in Gram-negative Sepsis and Causes Inflammation and Death in Mice J. Biol. Chem., April 12, 2002; 277(16): 14274 - 14280. [Abstract] [Full Text] [PDF]
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 S. Lehnardt, C. Lachance, S. Patrizi, S. Lefebvre, P. L. Follett, F. E. Jensen, P. A. Rosenberg, J. J. Volpe, and T. Vartanian The Toll-Like Receptor TLR4 Is Necessary for Lipopolysaccharide-Induced Oligodendrocyte Injury in the CNS J. Neurosci., April 1, 2002; 22(7): 2478 - 2486. [Abstract] [Full Text] [PDF]
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R. N. Fichorova, A. O. Cronin, E. Lien, D. J. Anderson, and R. R. Ingalls Response to Neisseria gonorrhoeae by Cervicovaginal Epithelial Cells Occurs in the Absence of Toll-Like Receptor 4-Mediated Signaling J. Immunol., March 1, 2002; 168(5): 2424 - 2432. [Abstract] [Full Text] [PDF]
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K. M. EDWARDS, M. H. CYNAMON, R. K. R. VOLADRI, C. C. HAGER, M. S. DESTEFANO, K. T. THAM, D. L. LAKEY, M. R. BOCHAN, and D. S. KERNODLE Iron-cofactored Superoxide Dismutase Inhibits Host Responses to Mycobacterium tuberculosis Am. J. Respir. Crit. Care Med., December 15, 2001; 164(12): 2213 - 2219. [Abstract] [Full Text] [PDF]
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C. A. Scanga, V. P. Mohan, K. Tanaka, D. Alland, J. L. Flynn, and J. Chan The Inducible Nitric Oxide Synthase Locus Confers Protection against Aerogenic Challenge of Both Clinical and Laboratory Strains of Mycobacterium tuberculosis in Mice Infect. Immun., December 1, 2001; 69(12): 7711 - 7717. [Abstract] [Full Text] [PDF]
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J. Warwick-Davies, A. J. Watson, G. E. Griffin, S. Krishna, and R. J. Shattock Enhancement of Mycobacterium tuberculosis-Induced Tumor Necrosis Factor Alpha Production from Primary Human Monocytes by an Activated T-Cell Membrane-Mediated Mechanism Infect. Immun., November 1, 2001; 69(11): 6580 - 6587. [Abstract] [Full Text] [PDF]
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A. E. Medvedev, P. Henneke, A. Schromm, E. Lien, R. Ingalls, M. J. Fenton, D. T. Golenbock, and S. N. Vogel Induction of Tolerance to Lipopolysaccharide and Mycobacterial Components in Chinese Hamster Ovary/CD14 Cells Is Not Affected by Overexpression of Toll-Like Receptors 2 or 4 J. Immunol., August 15, 2001; 167(4): 2257 - 2267. [Abstract] [Full Text] [PDF]
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E. H. Noss, R. K. Pai, T. J. Sellati, J. D. Radolf, J. Belisle, D. T. Golenbock, W. H. Boom, and C. V. Harding Toll-Like Receptor 2-Dependent Inhibition of Macrophage Class II MHC Expression and Antigen Processing by 19-kDa Lipoprotein of Mycobacterium tuberculosis J. Immunol., July 15, 2001; 167(2): 910 - 918. [Abstract] [Full Text] [PDF]
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B. W. Jones, T. K. Means, K. A. Heldwein, M. A. Keen, P. J. Hill, J. T. Belisle, and M. J. Fenton Different Toll-like receptor agonists induce distinct macrophage responses J. Leukoc. Biol., June 1, 2001; 69(6): 1036 - 1044. [Abstract] [Full Text] [PDF]
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