Transmembrane TNF protects mutant mice against intracellular bacterial infections, chronic inflammation and autoimmunity.
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.
Alexopoulou
Lena
L
Institute of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece.
Kranidioti
Ksanthi
K
Xanthoulea
Sofia
S
Denis
Maria
M
Kotanidou
Anastasia
A
Douni
Eleni
E
Blackshear
Perry J
PJ
Kontoyiannis
Dimitris L
DL
Kollias
George
G
D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology; D015551:Autoimmunity; D001424:Bacterial Infections / Q000276:immunology*; D015152:Blotting, Northern; D002462:Cell Membrane / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology*; D008198:Lymph Nodes / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D014409:Tumor Necrosis Factor-alpha