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Departments of
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Molecular Immunology and
Immunobiology, Immunex Corp., Seattle, WA 98101
The pleiotropic activities of the potent proinflammatory cytokine TNF are mediated by two structurally related, but functionally distinct, receptors, p55 and p75, that are coexpressed on most cell types. The majority of biologic responses classically attributed to TNF are mediated by p55. In contrast, p75 has been proposed to function as both a TNF antagonist by neutralizing TNF and as a TNF agonist by facilitating the interaction between TNF and p55 at the cell surface. We have examined the roles of p55 and p75 in mediating and modulating the activity of TNF in vivo by generating and examining mice genetically deficient in these receptors. Selective deficits in several host defense and inflammatory responses are observed in mice lacking p55 or both p55 and p75, but not in mice lacking p75. In these models, the activity of p55 is not impaired by the absence of p75, arguing against a physiologic role for p75 as an essential element of p55-mediated signaling. In contrast, exacerbated pulmonary inflammation and dramatically increased endotoxin induced serum TNF levels in mice lacking p75 suggest a dominant role for p75 in suppressing TNF-mediated inflammatory responses. In summary, these data help clarify the biologic roles of p55 and p75 in mediating and modulating the biologic activity of TNF and provide genetic evidence for an antagonistic role of p75 in vivo.
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R. G. Lorenz, D. D. Chaplin, K. G. McDonald, J. S. McDonough, and R. D. Newberry Isolated Lymphoid Follicle Formation Is Inducible and Dependent Upon Lymphotoxin-Sufficient B Lymphocytes, Lymphotoxin {beta} Receptor, and TNF Receptor I Function J. Immunol., June 1, 2003; 170(11): 5475 - 5482. [Abstract] [Full Text] [PDF] |
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J. Corredor, F. Yan, C. C. Shen, W. Tong, S. K. John, G. Wilson, R. Whitehead, and D. B. Polk Tumor necrosis factor regulates intestinal epithelial cell migration by receptor-dependent mechanisms Am J Physiol Cell Physiol, April 1, 2003; 284(4): C953 - C961. [Abstract] [Full Text] [PDF] |
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A. S. De Vriese Prevention and Treatment of Acute Renal Failure in Sepsis J. Am. Soc. Nephrol., March 1, 2003; 14(3): 792 - 805. [Full Text] [PDF] |
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G. S. Pryhuber, H. L. Huyck, R. Baggs, G. Oberdorster, and J. N. Finkelstein Induction of Chemokines by Low-Dose Intratracheal Silica Is Reduced in TNFR I (p55) Null Mice Toxicol. Sci., March 1, 2003; 72(1): 150 - 157. [Abstract] [Full Text] [PDF] |
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M. Pandey, G. Tuncman, G. S. Hotamisligil, and F. Samad Divergent Roles for p55 and p75 TNF-{alpha} Receptors in the Induction of Plasminogen Activator Inhibitor-1 Am. J. Pathol., March 1, 2003; 162(3): 933 - 941. [Abstract] [Full Text] [PDF] |
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J. Schumann, K. Muhlen, A. K. Kiemer, A. M. Vollmar, and G. Tiegs Parenchymal, But Not Leukocyte, TNF Receptor 2 Mediates T Cell-Dependent Hepatitis in Mice J. Immunol., February 15, 2003; 170(4): 2129 - 2137. [Abstract] [Full Text] [PDF] |
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K. Akassoglou, E. Douni, J. Bauer, H. Lassmann, G. Kollias, and L. Probert Exclusive tumor necrosis factor (TNF) signaling by the p75TNF receptor triggers inflammatory ischemia in the CNS of transgenic mice PNAS, January 21, 2003; 100(2): 709 - 714. [Abstract] [Full Text] [PDF] |
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J. H. Wang, M. Doyle, B. J. Manning, S. Blankson, Q. D. Wu, C. Power, R. Cahill, and H. P. Redmond Cutting Edge: Bacterial Lipoprotein Induces Endotoxin-Independent Tolerance to Septic Shock J. Immunol., January 1, 2003; 170(1): 14 - 18. [Abstract] [Full Text] [PDF] |
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L. M. Sedger, S. Hou, S. R. Osvath, M. B. Glaccum, J. J. Peschon, N. van Rooijen, and L. Hyland Bone Marrow B Cell Apoptosis During In Vivo Influenza Virus Infection Requires TNF-{alpha} and Lymphotoxin-{alpha} J. Immunol., December 1, 2002; 169(11): 6193 - 6201. [Abstract] [Full Text] [PDF] |
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M. A. Koay, J. W. Christman, L. J. Wudel, T. Allos, D.-S. Cheng, W. C. Chapman, and T. S. Blackwell Modulation of endotoxin-induced NF-kappa B activation in lung and liver through TNF type 1 and IL-1 receptors Am J Physiol Lung Cell Mol Physiol, December 1, 2002; 283(6): L1247 - L1254. [Abstract] [Full Text] [PDF] |
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A. Kanehiro, M. Lahn, M. J. Makela, A. Dakhama, A. Joetham, Y.-H. Rha, W. Born, and E. W. Gelfand Requirement for the p75 TNF-{alpha} Receptor 2 in the Regulation of Airway Hyperresponsiveness by {gamma}{delta} T Cells J. Immunol., October 15, 2002; 169(8): 4190 - 4197. [Abstract] [Full Text] [PDF] |
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A. Churg, J. Dai, H. Tai, C. Xie, and J. L. Wright Tumor Necrosis Factor-{alpha} Is Central to Acute Cigarette Smoke-induced Inflammation and Connective Tissue Breakdown Am. J. Respir. Crit. Care Med., September 15, 2002; 166(6): 849 - 854. [Abstract] [Full Text] |
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A. A. Ragab, J. L. Nalepka, Y. Bi, and E. M. Greenfield Cytokines synergistically induce osteoclast differentiation: support by immortalized or normal calvarial cells Am J Physiol Cell Physiol, September 1, 2002; 283(3): C679 - C687. [Abstract] [Full Text] [PDF] |
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T. Kagari, H. Doi, and T. Shimozato The Importance of IL-1{beta} and TNF-{alpha}, and the Noninvolvement of IL-6, in the Development of Monoclonal Antibody-Induced Arthritis J. Immunol., August 1, 2002; 169(3): 1459 - 1466. [Abstract] [Full Text] [PDF] |
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L. Li, A. Khansari, L. Shapira, D. T. Graves, and S. Amar Contribution of Interleukin-11 and Prostaglandin(s) in Lipopolysaccharide-Induced Bone Resorption In Vivo Infect. Immun., July 1, 2002; 70(7): 3915 - 3922. [Abstract] [Full Text] [PDF] |
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N. Cusson, S. Oikemus, E. D. Kilpatrick, L. Cunningham, and M. Kelliher The Death Domain Kinase RIP Protects Thymocytes from Tumor Necrosis Factor Receptor Type 2-induced Cell Death J. Exp. Med., July 1, 2002; 196(1): 15 - 26. [Abstract] [Full Text] [PDF] |
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H. Ji, A. Pettit, K. Ohmura, A. Ortiz-Lopez, V. Duchatelle, C. Degott, E. Gravallese, D. Mathis, and C. Benoist Critical Roles for Interleukin 1 and Tumor Necrosis Factor {alpha} in Antibody-induced Arthritis J. Exp. Med., July 1, 2002; 196(1): 77 - 85. [Abstract] [Full Text] [PDF] |
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P. N. Cunningham, H. M. Dyanov, P. Park, J. Wang, K. A. Newell, and R. J. Quigg Acute Renal Failure in Endotoxemia Is Caused by TNF Acting Directly on TNF Receptor-1 in Kidney J. Immunol., June 1, 2002; 168(11): 5817 - 5823. [Abstract] [Full Text] [PDF] |
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R. D. Newberry, J. S. McDonough, K. G. McDonald, and R. G. Lorenz Postgestational Lymphotoxin/Lymphotoxin {beta} Receptor Interactions Are Essential for the Presence of Intestinal B Lymphocytes J. Immunol., May 15, 2002; 168(10): 4988 - 4997. [Abstract] [Full Text] [PDF] |
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A. H. van Houwelingen, M. Kool, S. C. A. de Jager, F. A. M. Redegeld, D. van Heuven-Nolsen, A. D. Kraneveld, and F. P. Nijkamp Mast Cell-Derived TNF-{alpha} Primes Sensory Nerve Endings in a Pulmonary Hypersensitivity Reaction J. Immunol., May 15, 2002; 168(10): 5297 - 5302. [Abstract] [Full Text] [PDF] |
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J. R. Maxwell, C. Ruby, N. I. Kerkvliet, and A. T. Vella Contrasting the Roles of Costimulation and the Natural Adjuvant Lipopolysaccharide During the Induction of T Cell Immunity J. Immunol., May 1, 2002; 168(9): 4372 - 4381. [Abstract] [Full Text] [PDF] |
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S. Smith, D. Liggitt, E. Jeromsky, X. Tan, S. J. Skerrett, and C. B. Wilson Local Role for Tumor Necrosis Factor Alpha in the Pulmonary Inflammatory Response to Mycobacterium tuberculosis Infection Infect. Immun., April 1, 2002; 70(4): 2082 - 2089. [Abstract] [Full Text] [PDF] |
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P J Mease Tumour necrosis factor (TNF) in psoriatic arthritis: pathophysiology and treatment with TNF inhibitors Ann Rheum Dis, April 1, 2002; 61(4): 298 - 304. [Abstract] [Full Text] [PDF] |
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S. A. Schreyer, C. M. Vick, and R. C. LeBoeuf Loss of Lymphotoxin-alpha but Not Tumor Necrosis Factor-alpha Reduces Atherosclerosis in Mice J. Biol. Chem., March 29, 2002; 277(14): 12364 - 12368. [Abstract] [Full Text] [PDF] |
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W. Pan, G. Cornelissen, F. Halberg, and A. J. Kastin Functional Genomics of Sleep and Circadian Rhythm: Selected Contribution: Circadian rhythm of tumor necrosis factor-alpha uptake into mouse spinal cord J Appl Physiol, March 1, 2002; 92(3): 1357 - 1362. [Abstract] [Full Text] [PDF] |
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A. Wellmer, J. Gerber, J. Ragheb, G. Zysk, T. Kunst, A. Smirnov, W. Bruck, and R. Nau Effect of Deficiency of Tumor Necrosis Factor Alpha or Both of Its Receptors on Streptococcus pneumoniae Central Nervous System Infection and Peritonitis Infect. Immun., November 1, 2001; 69(11): 6881 - 6886. [Abstract] [Full Text] [PDF] |
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A. Oberholzer, C. Oberholzer, F.R. Bahjat, C. K. Edwards, and L. L. Moldawer Genetic determinants of lipopolysaccharide and D-galactosamine-mediated hepatocellular apoptosis and lethality Innate Immunity, October 1, 2001; 7(5): 375 - 380. [Abstract] [PDF] |
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D.T. Graves, M. Oskoui, S. Voleinikova, G. Naguib, S. Cai, T. Desta, A. Kakouras, and Y. Jiang Tumor Necrosis Factor Modulates Fibroblast Apoptosis, PMN Recruitment, and Osteoclast Formation in Response to P. gingivalis Infection Journal of Dental Research, October 1, 2001; 80(10): 1875 - 1879. [Abstract] [PDF] |
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