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The Role of Tuberous Sclerosis Complex 1 in Regulating Innate Immunity.
- Source :
-
Journal of Immunology . 4/15/2012, Vol. 188 Issue 8, p3658-3666. 9p. - Publication Year :
- 2012
-
Abstract
- The mechanisms that control TLR-induced responses, including endotoxin tolerance, have been not well understood. The tuberous sclerosis complex 1 (TSCl) is a tumor suppressor that inhibits the mammalian target of rapamycin (mTOR). We show in this study that deficiency of TSCl results in enhanced activation of not only mTOR complex 1 (mTORCl), but also JNKl/2, following LPS stimulation in macrophages. TSCI-deficient macrophages produce elevated proinflammatory cytokines and NO in response to multiple TLR Iigands. Such enhanced TLR-induced responses can be inhibited by reducing mTORCl and JNKl/2 activities with chemical inhibitors or small hairpin RNA, suggesting that TSCl negatively controls TLR responses through both mTORCl and JNKl/2. The impact of TSCl deficiency appeared not limited to TLRs, as NOD- and RIG-I/MDA-5-induced innate responses were also altered in TSCl-deficient macrophages. Furthermore, TSCl deficiency appears to cause impaired induction of endotoxin tolerance in vitro and in vivo, which is correlated with increased JNKl/2 activation and can be reversed by JNKl/2 inhibition. Our results reveal a critical role of TSCl in regulating innate immunity by negative control of mTORCl and JNKl/2 activation. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00221767
- Volume :
- 188
- Issue :
- 8
- Database :
- Academic Search Index
- Journal :
- Journal of Immunology
- Publication Type :
- Academic Journal
- Accession number :
- 77565996
- Full Text :
- https://doi.org/10.4049/jimmunol.1102187