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 language | English |
|---|---|
| Pages (from-to) | 333-339 |
| Number of pages | 7 |
| Journal | Journal of Experimental Medicine |
| Volume | 201 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Feb 7 2005 |
Fingerprint
All Science Journal Classification (ASJC) codes
- Immunology and Allergy
- Immunology
Cite this
Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling. / Shinohara, Hisaaki; Inoue, Akane; Toyama-Sorimachi, Noriko; Nagai, Yoshinori; Yasuda, Tomoharu; Suzuki, Hiromi; Horai, Reiko; Iwakura, Yoichiro; Yamamoto, Tadashi; Karasuyama, Hajime; Miyake, Kensuke; Yamanashi, Yuji.
In: Journal of Experimental Medicine, Vol. 201, No. 3, 07.02.2005, p. 333-339.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling
AU - Shinohara, Hisaaki
AU - Inoue, Akane
AU - Toyama-Sorimachi, Noriko
AU - Nagai, Yoshinori
AU - Yasuda, Tomoharu
AU - Suzuki, Hiromi
AU - Horai, Reiko
AU - Iwakura, Yoichiro
AU - Yamamoto, Tadashi
AU - Karasuyama, Hajime
AU - Miyake, Kensuke
AU - Yamanashi, Yuji
PY - 2005/2/7
Y1 - 2005/2/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=13644271366&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=13644271366&partnerID=8YFLogxK
U2 - 10.1084/jem.20041817
DO - 10.1084/jem.20041817
M3 - Article
C2 - 15699069
AN - SCOPUS:13644271366
VL - 201
SP - 333
EP - 339
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 3
ER -