Transmembrane TNF protects mutant mice against intracellular bacterial infections, chronic inflammation and autoimmunity

被引:99
作者
Alexopoulou, Lena
Kranidioti, Ksanthi
Xanthoulea, Sofia
Denis, Maria
Kotanidou, Anastasia
Douni, Eleni
Blackshear, Perry J.
Kontoyiannis, Dimitris L.
Kollias, George [1 ]
机构
[1] Biomed Sci Res Ctr Alexander Fleming, Inst Immunol, Vari 16672, Greece
[2] Univ Athens, Dept Crit Care & Pulm Serv, Evaggelismos Hosp, Athens, Greece
[3] Natl Inst Environm Hlth Sci, Off Clin Res, Res Triangle Pk, NC USA
[4] Natl Inst Environm Hlth Sci, Neurobiol Lab, Res Triangle Pk, NC USA
关键词
animal models; cell surface molecules; cytokines; lymphoid organs; neuroimmunology;
D O I
10.1002/eji.200635921
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:2768 / 2780
页数:13
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