The role of tuberous sclerosis complex 1 in regulating innate immunity.
Journal Article (Journal Article)
The mechanisms that control TLR-induced responses, including endotoxin tolerance, have been not well understood. The tuberous sclerosis complex 1 (TSC1) is a tumor suppressor that inhibits the mammalian target of rapamycin (mTOR). We show in this study that deficiency of TSC1 results in enhanced activation of not only mTOR complex 1 (mTORC1), but also JNK1/2, following LPS stimulation in macrophages. TSC1-deficient macrophages produce elevated proinflammatory cytokines and NO in response to multiple TLR ligands. Such enhanced TLR-induced responses can be inhibited by reducing mTORC1 and JNK1/2 activities with chemical inhibitors or small hairpin RNA, suggesting that TSC1 negatively controls TLR responses through both mTORC1 and JNK1/2. The impact of TSC1 deficiency appeared not limited to TLRs, as NOD- and RIG-I/MDA-5-induced innate responses were also altered in TSC1-deficient macrophages. Furthermore, TSC1 deficiency appears to cause impaired induction of endotoxin tolerance in vitro and in vivo, which is correlated with increased JNK1/2 activation and can be reversed by JNK1/2 inhibition. Our results reveal a critical role of TSC1 in regulating innate immunity by negative control of mTORC1 and JNK1/2 activation.
Full Text
Duke Authors
Cited Authors
- Pan, H; O'Brien, TF; Zhang, P; Zhong, X-P
Published Date
- April 15, 2012
Published In
Volume / Issue
- 188 / 8
Start / End Page
- 3658 - 3666
PubMed ID
- 22412198
Pubmed Central ID
- PMC3324625
Electronic International Standard Serial Number (EISSN)
- 1550-6606
Digital Object Identifier (DOI)
- 10.4049/jimmunol.1102187
Language
- eng
Conference Location
- United States