Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling

Hisaaki Shinohara, Akane Inoue, Noriko Toyama-Sorimachi, Yoshinori Nagai, Tomoharu Yasuda, Hiromi Suzuki, Reiko Horai, Yoichiro Iwakura, Tadashi Yamamoto, Hajime Karasuyama, Kensuke Miyake, Yuji Yamanashi

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68 Citations (Scopus)

Abstract

Endotoxin, a bacterial lipopolysaccharide (LPS), causes fatal septic shock via Toll-like receptor (TLR)4 on effector cells of innate immunity like macrophages, where it activates nuclear factor κB (NF-κB) and mitogen-activated protein (MAP) kinases to induce proinflammatory cytokines such as tumor necrosis factor (TNF)-α. Dok-1 and Dok-2 are adaptor proteins that negatively regulate Ras-Erk signaling downstream of protein tyrosine kinases (PTKs). Here, we demonstrate that LPS rapidly induced the tyrosine phosphorylation and adaptor function of these proteins. The stimulation with LPS of macrophages from mice lacking Dok-1 or Dok-2 induced elevated Erk activation, but not the other MAP kinases or NF-κB;, resulting in hyperproduction of TNF-α and nitric oxide. Furthermore, the mutant mice showed hyperproduction of TNF-α and hypersensitivity to LPS. However, macrophages from these mutant mice reacted normally to other pathogenic molecules, CpG oligodeoxynucleotides, poly(I:C) ribonucleotides, or Pam 3CSK4 lipopeptide, which activated cognate TLRs but induced no tyrosine phosphorylation of Dok-1 or Dok-2. Forced expression of either adaptor, but not a mutant having a Tyr/Phe substitution, in macrophages inhibited LPS-induced Erk activation and TNF-α production. Thus, Dok-1 and Dok-2 are essential negative regulators downstream of TLR4, implying a novel PTK-dependent pathway in innate immunity.

Original languageEnglish
Pages (from-to)333-339
Number of pages7
JournalJournal of Experimental Medicine
Volume201
Issue number3
DOIs
Publication statusPublished - Feb 7 2005

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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    Shinohara, H., Inoue, A., Toyama-Sorimachi, N., Nagai, Y., Yasuda, T., Suzuki, H., Horai, R., Iwakura, Y., Yamamoto, T., Karasuyama, H., Miyake, K., & Yamanashi, Y. (2005). Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling. Journal of Experimental Medicine, 201(3), 333-339. https://doi.org/10.1084/jem.20041817