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The Journal of Immunology, 1998, 160: 943-952.
Copyright © 1998 by The American Association of Immunologists

TNF Receptor-Deficient Mice Reveal Divergent Roles for p55 and p75 in Several Models of Inflammation

Jacques J. Peschon1,*, Dauphine S. Torrance{dagger}, Kim L. Stocking*, Moira B. Glaccum*, Carol Otten{dagger}, Cynthia R. Willis*, Keith Charrier*, Philip J. Morrissey*, Carol B. Ware2,* and Kendall M. Mohler{dagger}

Departments of * Molecular Immunology and {dagger} 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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J. P. Mizgerd, M. M. Lupa, J. Hjoberg, J. C. Vallone, H. B. Warren, J. P. Butler, and E. S. Silverman
Roles for early response cytokines during Escherichia coli pneumonia revealed by mice with combined deficiencies of all signaling receptors for TNF and IL-1
Am J Physiol Lung Cell Mol Physiol, June 1, 2004; 286(6): L1302 - L1310.
[Abstract] [Full Text] [PDF]

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 J. Virol.Home page
M. Suresh, X. Gao, C. Fischer, N. E. Miller, and K. Tewari
Dissection of Antiviral and Immune Regulatory Functions of Tumor Necrosis Factor Receptors in a Chronic Lymphocytic Choriomeningitis Virus Infection
J. Virol., April 15, 2004; 78(8): 3906 - 3918.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
T. W. Wright, G. S. Pryhuber, P. R. Chess, Z. Wang, R. H. Notter, and F. Gigliotti
TNF Receptor Signaling Contributes to Chemokine Secretion, Inflammation, and Respiratory Deficits during Pneumocystis Pneumonia
J. Immunol., February 15, 2004; 172(4): 2511 - 2521.
[Abstract] [Full Text] [PDF]

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 Arch DermatolHome page
G. Krueger and K. Callis
Potential of Tumor Necrosis Factor Inhibitors in Psoriasis and Psoriatic Arthritis
Arch Dermatol, February 1, 2004; 140(2): 218 - 225.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
T. E. Riehl, R. D. Newberry, R. G. Lorenz, and W. F. Stenson
TNFR1 mediates the radioprotective effects of lipopolysaccharide in the mouse intestine
Am J Physiol Gastrointest Liver Physiol, January 1, 2004; 286(1): G166 - G173.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
O. Tliba, S. Tliba, C. Da Huang, R. K. Hoffman, P. DeLong, R. A. Panettieri Jr., and Y. Amrani
Tumor Necrosis Factor {alpha} Modulates Airway Smooth Muscle Function via the Autocrine Action of Interferon {beta}
J. Biol. Chem., December 12, 2003; 278(50): 50615 - 50623.
[Abstract] [Full Text] [PDF]

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 FASEB J.Home page
Y. CHEN, Q. KE, Y. YANG, J. S. RANA, J. TANG, J. P. MORGAN, and Y.-F. XIAO
Cardiomyocytes overexpressing TNF-{alpha} attract migration of embryonic stem cells via activation of p38 and c-Jun amino-terminal kinase
FASEB J, December 1, 2003; 17(15): 2231 - 2239.
[Abstract] [Full Text] [PDF]

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 J. Virol.Home page
P. Lundberg, P. Welander, H. Openshaw, C. Nalbandian, C. Edwards, L. Moldawer, and E. Cantin
A Locus on Mouse Chromosome 6 That Determines Resistance to Herpes Simplex Virus Also Influences Reactivation, While an Unlinked Locus Augments Resistance of Female Mice
J. Virol., November 1, 2003; 77(21): 11661 - 11673.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
H. Chiu, C. R. Gardner, D. M. Dambach, J. A. Brittingham, S. K. Durham, J. D. Laskin, and D. L. Laskin
Role of p55 tumor necrosis factor receptor 1 in acetaminophen-induced antioxidant defense
Am J Physiol Gastrointest Liver Physiol, November 1, 2003; 285(5): G959 - G966.
[Abstract] [Full Text] [PDF]

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 Infect. Immun.Home page
T. A. Moore, M. L. Perry, A. G. Getsoian, C. L. Monteleon, A. L. Cogen, and T. J. Standiford
Increased Mortality and Dysregulated Cytokine Production in Tumor Necrosis Factor Receptor 1-Deficient Mice following Systemic Klebsiella pneumoniae Infection
Infect. Immun., September 1, 2003; 71(9): 4891 - 4900.
[Abstract] [Full Text] [PDF]

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 J. Appl. Physiol.Home page
H. Chen, O. Tliba, C. R. Van Besien, R. A. Panettieri Jr., and Y. Amrani
Selected Contribution: TNF-{alpha} modulates murine tracheal rings responsiveness to G-protein-coupled receptor agonists and KCl
J Appl Physiol, August 1, 2003; 95(2): 864 - 872.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
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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 Am. J. Physiol. Cell Physiol.Home page
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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 J. Am. Soc. Nephrol.Home page
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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 Toxicol SciHome page
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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 Am. J. Pathol.Home page
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. Immunol.Home page
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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 Proc. Natl. Acad. Sci. USAHome page
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. Immunol.Home page
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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 J. Immunol.Home page
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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 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
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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 J. Immunol.Home page
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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 Am. J. Respir. Crit. Care Med.Home page
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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 Am. J. Physiol. Cell Physiol.Home page
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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 J. Immunol.Home page
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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 Infect. Immun.Home page
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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 JEMHome page
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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 JEMHome page
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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 J. Immunol.Home page
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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 J. Immunol.Home page
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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 J. Immunol.Home page
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. Immunol.Home page
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]

Home page
 Infect. Immun.Home page
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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 Ann Rheum DisHome page
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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 J. Biol. Chem.Home page
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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 J. Appl. Physiol.Home page
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]

Home page
 Infect. Immun.Home page
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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 Innate ImmunityHome page
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]

Home page
 JDRHome page
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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