PMID- 11745395
OWN - NLM
STAT- MEDLINE
DCOM- 20020124
LR  - 20191105
IS  - 0014-2980 (Print)
IS  - 0014-2980 (Linking)
VI  - 31
IP  - 12
DP  - 2001 Dec
TI  - IRAK and TAK1 are required for IL-18-mediated signaling.
PG  - 3747-54
AB  - Interleukin-18 (IL-18), a pleiotropic cytokine produced by activated macrophages, 
      plays significant roles in the immune response, inducing the secretion of 
      IFN-gamma, TNF-alpha and IL-2, enhancing NK cell activity and potentiating the 
      differentiation of Th1 cells. The intercellular signal transduction pathways 
      through which IL-18 functions have not been thoroughly defined. We have generated 
      a mutant cell line, I1A, that lacks the IRAK protein. In this line which has low 
      or no expression of the other known IRAK family members, we find that the IL-1 
      receptor-associated kinase (IRAK) is essential for the activation of NFkappaB and 
      JNK in response to IL-18. Furthermore, the death domain, but not the kinase 
      activity of IRAK, is necessary for NFkappaB activation in response to IL-18. 
      Interestingly, the N-proximal undetermined region of IRAK is necessary for 
      NFkappaB activation, but not for JNK activation in response to IL-18, indicating 
      IRAK may be a branchpoint in IL-18 signaling. In addition to IRAK, we implicate 
      two other components in IL-18 signaling, TAK1 (TGF-beta-activated kinase 1) and 
      its activator and substrate TAB1. A dominant negative mutant of TAK1 inhibits the 
      IL-18-mediated NFkappaB activation, while IL-18 stimulation leads to the 
      phosphorylation of TAB1. Finally, analysis of IL-18 signaling in 
      IL-1-unresponsive mutant cell lines suggests that the IL-1- and IL-18-mediated 
      pathways are similar, but may not be identical.
FAU - Wald, D
AU  - Wald D
AD  - Lerner Research Institute, The Cleveland Clinic Foundation and Department of 
      Pathology, Case Western Reserve University, Cleveland, OH 44195, USA.
FAU - Commane, M
AU  - Commane M
FAU - Stark, G R
AU  - Stark GR
FAU - Li, X
AU  - Li X
LA  - eng
GR  - GM 6000020/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - Germany
TA  - Eur J Immunol
JT  - European journal of immunology
JID - 1273201
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Carrier Proteins)
RN  - 0 (Interleukin-1)
RN  - 0 (Interleukin-18)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (NF-kappa B)
RN  - 0 (TAB1 protein, MAPKKK activator, vertebrate)
RN  - 0 (TAB1 protein, human)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.11.1 (Interleukin-1 Receptor-Associated Kinases)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.25 (MAP Kinase Kinase Kinases)
RN  - EC 2.7.11.25 (MAP kinase kinase kinase 7)
SB  - IM
MH  - *Adaptor Proteins, Signal Transducing
MH  - Carrier Proteins/physiology
MH  - Cells, Cultured
MH  - Humans
MH  - Interleukin-1/pharmacology
MH  - Interleukin-1 Receptor-Associated Kinases
MH  - Interleukin-18/*pharmacology
MH  - *Intracellular Signaling Peptides and Proteins
MH  - JNK Mitogen-Activated Protein Kinases
MH  - MAP Kinase Kinase Kinases/*physiology
MH  - Mitogen-Activated Protein Kinases/metabolism
MH  - NF-kappa B/metabolism
MH  - Phosphorylation
MH  - Protein Kinases/*physiology
MH  - *Signal Transduction
EDAT- 2001/12/18 10:00
MHDA- 2002/01/25 10:01
CRDT- 2001/12/18 10:00
PHST- 2001/12/18 10:00 [pubmed]
PHST- 2002/01/25 10:01 [medline]
PHST- 2001/12/18 10:00 [entrez]
AID - 10.1002/1521-4141(200112)31:12<3747::AID-IMMU3747>3.0.CO;2-E [pii]
AID - 10.1002/1521-4141(200112)31:12<3747::aid-immu3747>3.0.co;2-e [doi]
PST - ppublish
SO  - Eur J Immunol. 2001 Dec;31(12):3747-54. doi: 
      10.1002/1521-4141(200112)31:12<3747::aid-immu3747>3.0.co;2-e.