Τίτλος:
Transmembrane TNF protects mutant mice against intracellular bacterial infections, chronic inflammation and autoimmunity
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Using targeted mutagenesis in mice, we have blocked shedding of endogenous murine TNF by deleting its cleavage site. Mutant mice produce physiologically regulated levels of transmembrane TNF (tmTNF), which suffice to support thymocyte proliferation but cannot substitute for the hepatotoxic activities of wild-type TNF following LPS/D-galactosamine challenge in vivo and are not sufficient to support secondary lymphoid organ structure and function. Notably, however, tmTNF is capable of exerting anti-Listerial host defenses while remaining inadequate to mediate arthritogenic functions, as tested in the tristetraprolin-deficient model of TNF-dependent arthritis. Most interestingly, in the EAE model of autoimmune demyelination, tmTNF suppresses disease onset and progression and retains the autoimmune suppressive properties of wild-type TNF. Together, these results indicate that tmTNF preserves a subset of the beneficial activities of TNF while lacking detrimental effects. These data support the hypothesis that selective targeting of soluble TNF may offer several advantages over complete blockade of TNF in the treatment of chronic inflammation and autoimmunity. © 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
Συγγραφείς:
Alexopoulou, L.
Kranidioti, K.
Xanthoulea, S.
Denis, M.
Kotanidou, A.
Douni, E.
Blackshear, P.J.
Kontoyiannis, D.L.
Kollias, G.
Περιοδικό:
European Journal of Immunology
Λέξεις-κλειδιά:
galactosamine; lipopolysaccharide; tristetraprolin; tumor necrosis factor, animal cell; animal experiment; animal model; animal tissue; arthritis; article; autoimmunity; bacterial infection; cell proliferation; chronic inflammation; controlled study; demyelination; disease course; enzyme linked immunosorbent assay; flow cytometry; host resistance; immunization; immunohistochemistry; in vivo study; Listeria monocytogenes; listeriosis; lymphocyte proliferation; lymphoid organ; mouse; mouse mutant; mutagenesis; nonhuman; Northern blotting; phenotype; priority journal; protection; protein function; T lymphocyte; thymocyte; wild type, Animals; Arthritis, Experimental; Autoimmunity; Bacterial Infections; Blotting, Northern; Cell Membrane; Encephalomyelitis, Autoimmune, Experimental; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Immunohistochemistry; Inflammation; Lymph Nodes; Mice; Mice, Transgenic; Tumor Necrosis Factor-alpha
DOI:
10.1002/eji.200635921
