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,
,,
,¶,¶,
*
Institute for Human Gene Therapy, Departments of
Molecular and Cellular Engineering and
Microbiology, and
Wistar Institute, University of Pennsylvania, and
¶ Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104
Toll-like receptors (TLRs) have been implicated in the regulation
of host responses to microbial Ags. This study characterizes the role
of TLR4 in the innate immune response to intrapulmonary administration
of Haemophilus influenzae in the mouse. Two different
strains of mice efficiently cleared aerosolized H.
influenzae concurrent with a brisk elaboration of IL-1
,
IL-6, TNF-
, macrophage-inflammatory protein (MIP)-1, and MIP-2 in
bronchoalveolar lavage and a corresponding mobilization of
intrapulmonary neutrophils. Congenic strains of mice deficient in TLR4
demonstrated a substantial delay in clearance of H.
influenzae with diminished IL-1, IL-6, TNF-, MIP-1,
and MIP-2 in bronchoalveolar lavage and a notable absence of
intrapulmonary neutrophils. In TLR4-expressing animals, but not
TLR4-deficient animals, TNF- and MIP-1 expression was
up-regulated in epithelial cells of the conducting airway in response
to H. influenzae which was preceded by an apparent
activation of the NF-
B pathway in these cells based on the findings
of decreased overall IB and an increase in its phosphorylated form.
This study demonstrates a critical role of TLR4 in mediating an
effective innate immune response to H. influenzae in the
lung. This suggests that the airway epithelia might contribute to
sensing of H. influenzae infection and signaling the
innate immune response.
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J. S. Lee, C. W. Frevert, G. Matute-Bello, M. M. Wurfel, V. A. Wong, S.-M. Lin, J. Ruzinski, S. Mongovin, R. B. Goodman, and T. R. Martin TLR-4 pathway mediates the inflammatory response but not bacterial elimination in E. coli pneumonia Am J Physiol Lung Cell Mol Physiol, November 1, 2005; 289(5): L731 - L738. [Abstract] [Full Text] [PDF]
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C. S. Berenson, T. F. Murphy, C. T. Wrona, and S. Sethi Outer Membrane Protein P6 of Nontypeable Haemophilus influenzae Is a Potent and Selective Inducer of Human Macrophage Proinflammatory Cytokines Infect. Immun., May 1, 2005; 73(5): 2728 - 2735. [Abstract] [Full Text] [PDF]
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E. Lorenz, D. C. Chemotti, A. L. Jiang, and L. D. McDougal Differential Involvement of Toll-Like Receptors 2 and 4 in the Host Response to Acute Respiratory Infections with Wild-Type and Mutant Haemophilus influenzae Strains Infect. Immun., April 1, 2005; 73(4): 2075 - 2082. [Abstract] [Full Text] [PDF]
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 A. J. Ratner, E. S. Lysenko, M. N. Paul, and J. N. Weiser Synergistic proinflammatory responses induced by polymicrobial colonization of epithelial surfaces PNAS, March 1, 2005; 102(9): 3429 - 3434. [Abstract] [Full Text] [PDF]
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D. P. Widney, Y. Hu, A. K. Foreman-Wykert, K. C. Bui, T. T. Nguyen, B. Lu, C. Gerard, J. F. Miller, and J. B. Smith CXCR3 and Its Ligands Participate in the Host Response to Bordetella bronchiseptica Infection of the Mouse Respiratory Tract but Are Not Required for Clearance of Bacteria from the Lung Infect. Immun., January 1, 2005; 73(1): 485 - 493. [Abstract] [Full Text] [PDF]
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P. B. Mann, K. D. Elder, M. J. Kennett, and E. T. Harvill Toll-Like Receptor 4-Dependent Early Elicited Tumor Necrosis Factor Alpha Expression Is Critical for Innate Host Defense against Bordetella bronchiseptica Infect. Immun., November 1, 2004; 72(11): 6650 - 6658. [Abstract] [Full Text] [PDF]
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M. Laan, S. Bozinovski, and G. P. Anderson Cigarette Smoke Inhibits Lipopolysaccharide-Induced Production of Inflammatory Cytokines by Suppressing the Activation of Activator Protein-1 in Bronchial Epithelial Cells J. Immunol., September 15, 2004; 173(6): 4164 - 4170. [Abstract] [Full Text] [PDF]
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H. P. Jia, J. N. Kline, A. Penisten, M. A. Apicella, T. L. Gioannini, J. Weiss, and P. B. McCray Jr. Endotoxin responsiveness of human airway epithelia is limited by low expression of MD-2 Am J Physiol Lung Cell Mol Physiol, August 1, 2004; 287(2): L428 - L437. [Abstract] [Full Text] [PDF]
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S. J. Skerrett, H. D. Liggitt, A. M. Hajjar, R. K. Ernst, S. I. Miller, and C. B. Wilson Respiratory epithelial cells regulate lung inflammation in response to inhaled endotoxin Am J Physiol Lung Cell Mol Physiol, July 1, 2004; 287(1): L143 - L152. [Abstract] [Full Text] [PDF]
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 M. G. Netea, C. van der Graaf, J. W. M. Van der Meer, and B. J. Kullberg Toll-like receptors and the host defense against microbial pathogens: bringing specificity to the innate-immune system J. Leukoc. Biol., May 1, 2004; 75(5): 749 - 755. [Abstract] [Full Text] [PDF]
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S. J. Skerrett, H. D. Liggitt, A. M. Hajjar, and C. B. Wilson Cutting Edge: Myeloid Differentiation Factor 88 Is Essential for Pulmonary Host Defense against Pseudomonas aeruginosa but Not Staphylococcus aureus J. Immunol., March 15, 2004; 172(6): 3377 - 3381. [Abstract] [Full Text] [PDF]
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S. Fernandez, P. Jose, M. G. Avdiushko, A. M. Kaplan, and D. A. Cohen Inhibition of IL-10 Receptor Function in Alveolar Macrophages by Toll-Like Receptor Agonists J. Immunol., February 15, 2004; 172(4): 2613 - 2620. [Abstract] [Full Text] [PDF]
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J. Branger, S. Knapp, S. Weijer, J. C. Leemans, J. M. Pater, P. Speelman, S. Florquin, and T. van der Poll Role of Toll-Like Receptor 4 in Gram-Positive and Gram-Negative Pneumonia in Mice Infect. Immun., February 1, 2004; 72(2): 788 - 794. [Abstract] [Full Text] [PDF]
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S. C. Higgins, E. C. Lavelle, C. McCann, B. Keogh, E. McNeela, P. Byrne, B. O'Gorman, A. Jarnicki, P. McGuirk, and K. H. G. Mills Toll-Like Receptor 4-Mediated Innate IL-10 Activates Antigen-Specific Regulatory T Cells and Confers Resistance to Bordetella pertussis by Inhibiting Inflammatory Pathology J. Immunol., September 15, 2003; 171(6): 3119 - 3127. [Abstract] [Full Text] [PDF]
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 W. E. Swords, P. A. Jones, and M. A. Apicella Review: The lipo-oligosaccharides of Haemophilus influenzae: an interesting array of characters Innate Immunity, June 1, 2003; 9(3): 131 - 144. [Abstract] [PDF]
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R. B. Oliveira, M. T. Ochoa, P. A. Sieling, T. H. Rea, A. Rambukkana, E. N. Sarno, and R. L. Modlin Expression of Toll-Like Receptor 2 on Human Schwann Cells: a Mechanism of Nerve Damage in Leprosy Infect. Immun., March 1, 2003; 71(3): 1427 - 1433. [Abstract] [Full Text] [PDF]
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S. Yi, W. J. Hawthorne, A. M. Lehnert, H. Ha, J. K. W. Wong, N. van Rooijen, K. Davey, A. T. Patel, S. N. Walters, A. Chandra, et al. T Cell-Activated Macrophages Are Capable of Both Recognition and Rejection of Pancreatic Islet Xenografts J. Immunol., March 1, 2003; 170(5): 2750 - 2758. [Abstract] [Full Text] [PDF]
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H. Weighardt, S. Kaiser-Moore, R. M. Vabulas, C. J. Kirschning, H. Wagner, and B. Holzmann Cutting Edge: Myeloid Differentiation Factor 88 Deficiency Improves Resistance Against Sepsis Caused by Polymicrobial Infection J. Immunol., September 15, 2002; 169(6): 2823 - 2827. [Abstract] [Full Text] [PDF]
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D. Warburton Sound the Tocsin! Beware Adverse Effects of Lung Inflammation Early in Gestation Am. J. Respir. Crit. Care Med., March 15, 2002; 165(6): 741 - 742. [Full Text] [PDF]
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