The role of tuberous sclerosis complex 1 in regulating innate immunity

• Published in: The Journal of immunology (1950) 2012-04, Vol.188 (8), p.3658-3666
• Main Authors: Pan, Hongjie, O'Brien, Thomas F, Zhang, Ping, Zhong, Xiao-Ping
• Format: Article
• Language: English
• Subjects: Animals; Cytokines - biosynthesis; Cytokines - immunology; Gene Expression Regulation - immunology; Humans; Immunity, Innate; Lipopolysaccharides - pharmacology; Macrophages - drug effects; Macrophages - immunology; Macrophages - pathology; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Transgenic; Mitogen-Activated Protein Kinase 8 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 8 - genetics; Mitogen-Activated Protein Kinase 8 - immunology; Mitogen-Activated Protein Kinase 9 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 9 - genetics; Mitogen-Activated Protein Kinase 9 - immunology; Multiprotein Complexes; Nitric Oxide - biosynthesis; Phagocytosis - drug effects; Phagocytosis - immunology; Protein Kinase Inhibitors - pharmacology; Proteins - genetics; Proteins - immunology; RNA, Small Interfering - genetics; RNA, Small Interfering - immunology; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Suppressor Proteins - deficiency; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1102187

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.