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*
Lipid Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
Maxwell Finland Laboratory for Infectious Diseases, Department of Medicine, Boston Medical Center and Boston University School of Medicine, Boston, MA 02118; and
Leukocyte Biology and Inflammation Program, Renal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
Gram-negative bacteria and the LPS constituent of their outer
membranes stimulate the release of inflammatory mediators believed to
be responsible for the clinical manifestations of septic shock. The
GPI-linked membrane protein, CD14, initiates the signaling cascade
responsible for the induction of this inflammatory response by LPS. In
this paper, we report the generation and characterization of CD14-null
mice in which the entire coding region of CD14 was deleted. As
expected, LPS failed to elicit TNF-
and IL-6 production in
macrophages taken from these animals, and this loss in responsiveness
is associated with impaired activation of both the NF-
B and the
c-Jun N-terminal mitogen-activated protein kinase pathways. The binding
and uptake of heat-killed Escherichia coli, measured by
FACS analysis, did not differ between CD14-null and wild-type
macrophages. However, in contrast to the findings with LPS, whole
E. coli stimulated similar levels of TNF- release
from CD14-null and wild-type macrophages at a dose of 10 bioparticles
per cell. This effect was dose dependent, and at lower bacterial
concentrations CD14-deficient macrophages produced significantly less
TNF- than wild type. Approximately half of this CD14-independent
response appeared to be mediated by CD11b/CD18, as demonstrated by
receptor blockade using neutrophil inhibitory factor. An inhibitor of
phagocytosis, cytochalasin B, abrogated the induction of TNF- in
CD14-deficient macrophages by E. coli. These data
indicate that CD14 is essential for macrophage responses to free LPS,
whereas other receptors, including CD11b/CD18, can compensate for the
loss of CD14 in response to whole bacteria.
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L. E. Yauch, M. K. Mansour, S. Shoham, J. B. Rottman, and S. M. Levitz Involvement of CD14, Toll-Like Receptors 2 and 4, and MyD88 in the Host Response to the Fungal Pathogen Cryptococcus neoformans In Vivo Infect. Immun., September 1, 2004; 72(9): 5373 - 5382. [Abstract] [Full Text] [PDF]
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J. Roman, J. D. Ritzenthaler, B. Boles, M. Lois, and S. Roser-Page Lipopolysaccharide induces expression of fibronectin {alpha}5{beta}1-integrin receptors in human monocytic cells in a protein kinase C-dependent fashion Am J Physiol Lung Cell Mol Physiol, July 1, 2004; 287(1): L239 - L249. [Abstract] [Full Text] [PDF]
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J. F. Alcorn and J. R. Wright Surfactant protein A inhibits alveolar macrophage cytokine production by CD14-independent pathway Am J Physiol Lung Cell Mol Physiol, January 1, 2004; 286(1): L129 - L136. [Abstract] [Full Text] [PDF]
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K. Sau, S. S. Mambula, E. Latz, P. Henneke, D. T. Golenbock, and S. M. Levitz The Antifungal Drug Amphotericin B Promotes Inflammatory Cytokine Release by a Toll-like Receptor- and CD14-dependent Mechanism J. Biol. Chem., September 26, 2003; 278(39): 37561 - 37568. [Abstract] [Full Text] [PDF]
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K. J. Moore, J. El Khoury, L. A. Medeiros, K. Terada, C. Geula, A. D. Luster, and M. W. Freeman A CD36-initiated Signaling Cascade Mediates Inflammatory Effects of beta -Amyloid J. Biol. Chem., November 27, 2002; 277(49): 47373 - 47379. [Abstract] [Full Text] [PDF]
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K. K. Yang, B. G. Dorner, U. Merkel, B. Ryffel, C. Schutt, D. Golenbock, M. W. Freeman, and R. S. Jack Neutrophil Influx in Response to a Peritoneal Infection with Salmonella Is Delayed in Lipopolysaccharide-Binding Protein or CD14-Deficient Mice J. Immunol., October 15, 2002; 169(8): 4475 - 4480. [Abstract] [Full Text] [PDF]
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S. S. Mambula, K. Sau, P. Henneke, D. T. Golenbock, and S. M. Levitz Toll-like Receptor (TLR) Signaling in Response to Aspergillus fumigatus J. Biol. Chem., October 11, 2002; 277(42): 39320 - 39326. [Abstract] [Full Text] [PDF]
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P. Henneke, O. Takeuchi, R. Malley, E. Lien, R. R. Ingalls, M. W. Freeman, T. Mayadas, V. Nizet, S. Akira, D. L. Kasper, et al. Cellular Activation, Phagocytosis, and Bactericidal Activity Against Group B Streptococcus Involve Parallel Myeloid Differentiation Factor 88-Dependent and Independent Signaling Pathways J. Immunol., October 1, 2002; 169(7): 3970 - 3977. [Abstract] [Full Text] [PDF]
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 G. L. Su Lipopolysaccharides in liver injury: molecular mechanisms of Kupffer cell activation Am J Physiol Gastrointest Liver Physiol, August 1, 2002; 283(2): G256 - G265. [Abstract] [Full Text] [PDF]
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M. M. Monick, L. Powers, N. Butler, T. Yarovinsky, and G. W. Hunninghake Interaction of matrix with integrin receptors is required for optimal LPS-induced MAP kinase activation Am J Physiol Lung Cell Mol Physiol, August 1, 2002; 283(2): L390 - L402. [Abstract] [Full Text] [PDF]
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 T. K. Varma, C. Y. Lin, T. E. Toliver-Kinsky, and E. R. Sherwood Endotoxin-Induced Gamma Interferon Production: Contributing Cell Types and Key Regulatory Factors Clin. Vaccine Immunol., May 1, 2002; 9(3): 530 - 543. [Abstract] [Full Text] [PDF]
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S. Radulovic, P. W. Price, M. S. Beier, J. Gaywee, J. A. Macaluso, and A. Azad Rickettsia-Macrophage Interactions: Host Cell Responses to Rickettsia akari and Rickettsia typhi Infect. Immun., May 1, 2002; 70(5): 2576 - 2582. [Abstract] [Full Text] [PDF]
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 D. A. Schwartz The Genetics of Innate Immunity Chest, March 1, 2002; 121 (2009): 62S - 68S. [Abstract] [Full Text] [PDF]
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 M. W. Hornef, T. Frisan, A. Vandewalle, S. Normark, and A. Richter-Dahlfors Toll-like Receptor 4 Resides in the Golgi Apparatus and Colocalizes with Internalized Lipopolysaccharide in Intestinal Epithelial Cells J. Exp. Med., February 25, 2002; 195(5): 559 - 570. [Abstract] [Full Text] [PDF]
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 J. Zweigner, H.-J. Gramm, O. C. Singer, K. Wegscheider, and R. R. Schumann High concentrations of lipopolysaccharide-binding protein in serum of patients with severe sepsis or septic shock inhibit the lipopolysaccharide response in human monocytes Blood, December 15, 2001; 98(13): 3800 - 3808. [Abstract] [Full Text] [PDF]
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M. Bernheiden, J.-M. Heinrich, G. Minigo, C. Schutt, F. Stelter, M. Freeman, D. Golenbock, and R. S. Jack LBP, CD14, TLR4 and the murine innate immune response to a peritoneal Salmonella infection Innate Immunity, December 1, 2001; 7(6): 447 - 450. [Abstract] [PDF]
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 M. G. Schwacha, C. P. Schneider, K. I. Bland, and I. H. Chaudry Resistance of macrophages to the suppressive effect of interleukin-10 following thermal injury Am J Physiol Cell Physiol, October 1, 2001; 281(4): C1180 - C1187. [Abstract] [Full Text] [PDF]
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 N. Silverman and T. Maniatis NF-{kappa}B signaling pathways in mammalian and insect innate immunity Genes & Dev., September 15, 2001; 15(18): 2321 - 2342. [Full Text] [PDF]
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S. Sanlioglu, C. M. Williams, L. Samavati, N. S. Butler, G. Wang, P. B. McCray Jr., T. C. Ritchie, G. W. Hunninghake, E. Zandi, and J. F. Engelhardt Lipopolysaccharide Induces Rac1-dependent Reactive Oxygen Species Formation and Coordinates Tumor Necrosis Factor-alpha Secretion through IKK Regulation of NF-kappa B J. Biol. Chem., August 3, 2001; 276(32): 30188 - 30198. [Abstract] [Full Text] [PDF]
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