Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection.
The multiple biological activities of tumor necrosis factor (TNF) are mediated by two distinct cell surface receptors of 55 kd (TNFRp55) and 75 kd (TNFRp75). Using gene targeting, we generated a TNFRp55-deficient mouse strain. Cells from TNFRp55-/-mutant mice lack expression of TNFRp55 but display normal numbers of high affinity TNFRp75 molecules. Thymocyte development and lymphocyte populations are unaltered, and clonal deletion of potentially self-reactive T cells is not impaired. However, TNF signaling is largely abolished, as judged by the failure of TNF to induce NF-kappa B in T lymphocytes from TNFRp55-deficient mice. The loss of TNFRp55 function renders mice resistant to lethal dosages of either lipopolysaccharides or S. aureus enterotoxin B. In contrast, TNFRp55-deficient mice are severely impaired to clear L. monocytogenes and readily succumb to infection. Thus, the 55 kd TNFR plays a decisive role in the host's defense against microorganisms and their pathogenic factors.
Department of Medical Biophysics, University of Toronto, Princess Margaret Hospital, Canada.
K
K
Pfeffer
T
T
Matsuyama
T M
TM
Kündig
A
A
Wakeham
K
K
Kishihara
A
A
Shahinian
K
K
Wiegmann
P S
PS
Ohashi
M
M
Krönke
T W
TW
Mak
D000818:Animals; D001483:Base Sequence; D002467:Cell Nucleus / Q000378:metabolism; D003001:Cloning, Molecular; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000633:toxicity; D008088:Listeriosis / Q000276:immunology* / Q000503:physiopathology; D008099:Liver / Q000473:pathology; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D008970:Molecular Weight; D016328:NF-kappa B / Q000378:metabolism; D009838:Oligodeoxyribonucleotides; D016133:Polymerase Chain Reaction / Q000379:methods; D011869:Radioligand Assay; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D012772:Shock, Septic / Q000276:immunology* / Q000473:pathology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
D008070:Lipopolysaccharides; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha