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The role of tuberous sclerosis complex 1 in regulating innate immunity.

Publication ,  Journal Article
Pan, H; O'Brien, TF; Zhang, P; Zhong, X-P
Published in: J Immunol
April 15, 2012

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.

Duke Scholars

Published In

J Immunol

DOI

EISSN

1550-6606

Publication Date

April 15, 2012

Volume

188

Issue

8

Start / End Page

3658 / 3666

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tuberous Sclerosis Complex 1 Protein
  • TOR Serine-Threonine Kinases
  • Signal Transduction
  • RNA, Small Interfering
  • Proteins
  • Protein Kinase Inhibitors
  • Phagocytosis
  • Nitric Oxide
  • Multiprotein Complexes
 

Citation

APA
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MLA
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Pan, H., O’Brien, T. F., Zhang, P., & Zhong, X.-P. (2012). The role of tuberous sclerosis complex 1 in regulating innate immunity. J Immunol, 188(8), 3658–3666. https://doi.org/10.4049/jimmunol.1102187
Pan, Hongjie, Thomas F. O’Brien, Ping Zhang, and Xiao-Ping Zhong. “The role of tuberous sclerosis complex 1 in regulating innate immunity.J Immunol 188, no. 8 (April 15, 2012): 3658–66. https://doi.org/10.4049/jimmunol.1102187.
Pan H, O’Brien TF, Zhang P, Zhong X-P. The role of tuberous sclerosis complex 1 in regulating innate immunity. J Immunol. 2012 Apr 15;188(8):3658–66.
Pan, Hongjie, et al. “The role of tuberous sclerosis complex 1 in regulating innate immunity.J Immunol, vol. 188, no. 8, Apr. 2012, pp. 3658–66. Pubmed, doi:10.4049/jimmunol.1102187.
Pan H, O’Brien TF, Zhang P, Zhong X-P. The role of tuberous sclerosis complex 1 in regulating innate immunity. J Immunol. 2012 Apr 15;188(8):3658–3666.

Published In

J Immunol

DOI

EISSN

1550-6606

Publication Date

April 15, 2012

Volume

188

Issue

8

Start / End Page

3658 / 3666

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tuberous Sclerosis Complex 1 Protein
  • TOR Serine-Threonine Kinases
  • Signal Transduction
  • RNA, Small Interfering
  • Proteins
  • Protein Kinase Inhibitors
  • Phagocytosis
  • Nitric Oxide
  • Multiprotein Complexes