Altered thymic selection by overexpressing cellular FLICE inhibitory protein in T cells causes lupus-like syndrome in a BALB/c but not C57BL/6 strain Journal Article
| Authors: | Qiao, G.; Li, Z.; Minto, A. W.; Shia, J.; Yang, L.; Bao, L.; Tschopp, J.; Gao, J. X.; Wang, J.; Quigg, R. J.; Zhang, J. |
| Article Title: | Altered thymic selection by overexpressing cellular FLICE inhibitory protein in T cells causes lupus-like syndrome in a BALB/c but not C57BL/6 strain |
| Abstract: | The cellular FLICE inhibitory protein (c-FLIP) is an endogenous inhibitor of the caspase-8 proapoptotic signaling pathway downstream of death receptors. Recent evidence indicates that the long form of c-FLIP (c-FLIP L) is required for proliferation and effector T-cell development. However, the role of c-FLIP L in triggering autoimmunity has not been carefully analyzed. We now report that c-FLIP L transgenic (Tg) mice develop splenomegaly, lymphadenopathy, multiorgan infiltration, high titers of auto-antibodies, and proliferative glomerulonephritis with immune complex deposition in a strain-dependent manner. The development of autoimmunity requires CD4 T cells and may result from impaired thymic selection. At the molecular level, c-FLIP L overexpression inhibits the chain-associated protein tyrosine kinase of 70 kDa (ZAP-70) activation, thus impairing the signaling pathway derived from ZAP-70 required for thymic selection. Therefore, we have identified c-FLIP L as a susceptibility factor under the influence of epistatic modifiers for the development of autoimmunity. © 2010 Macmillan Publishers Limited. All rights reserved. |
| Keywords: | signal transduction; controlled study; protein expression; nonhuman; cell proliferation; t lymphocyte; t-lymphocytes; animal cell; mouse; phenotype; animals; mice; animal tissue; apoptosis; enzyme inhibition; mice, inbred balb c; mice, inbred c57bl; transgenic mouse; mus musculus; b-lymphocytes; mice, transgenic; lymphocyte activation; cytokines; dendritic cells; bagg albino mouse; thymus gland; splenomegaly; cd4+ t lymphocyte; autoimmunity; t-lymphocyte subsets; c57bl 6 mouse; autoantibody; autoantibodies; lymphadenopathy; protein kinase zap 70; zap-70 protein-tyrosine kinase; transgenes; antibody titer; t-cell activation; lupus erythematosus, systemic; flice inhibitory protein; casp8 and fadd-like apoptosis regulating protein; immune complex deposition; epistasis; lupus like syndrome; natural selection; proliferative glomerulonephritis |
| Journal Title: | Cell Death and Differentiation |
| Volume: | 17 |
| Issue: | 3 |
| ISSN: | 1350-9047 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2010-03-01 |
| Start Page: | 522 |
| End Page: | 533 |
| Language: | English |
| DOI: | 10.1038/cdd.2009.143 |
| PUBMED: | 19816511 |
| PROVIDER: | scopus |
| PMCID: | PMC2822025 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 20 April 2011" - "CODEN: CDDIE" - "Source: Scopus" |
