PMID- 22042853
OWN - NLM
STAT- MEDLINE
DCOM- 20120125
LR  - 20220316
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 108
IP  - 45
DP  - 2011 Nov 8
TI  - Crucial role for TNF receptor-associated factor 2 (TRAF2) in regulating NFkappaB2 
      signaling that contributes to autoimmunity.
PG  - 18354-9
LID - 10.1073/pnas.1109427108 [doi]
AB  - TNF receptor-associated factor 2 (TRAF2) is a key intracellular signaling 
      mediator that acts downstream of not only TNFalpha but also various members of the 
      TNFalpha superfamily. Here, we report that, despite their lack of TNFalpha signaling, 
      TRAF2(-/-)TNFalpha(-/-) mice develop an inflammatory disorder characterized by 
      autoantibody accumulation and organ infiltration by T cells with the phenotypes 
      of activated, effector, and memory cells. RAG1(-/-) mice reconstituted with 
      TRAF2(-/-)TNFalpha(-/-) bone marrow cells showed increased numbers of hyperactive T 
      cells and rapidly developed progressive and eventually lethal inflammation. No 
      inflammation was observed in RAG1(-/-) mice reconstituted with 
      TRAF2(-/-)TNFalpha(-/-)T-cell receptor beta(-/-) or TRAF2(-/-)TNFalpha(-/-)NFkappaB-induced 
      kinase(+/-) bone marrow cells. The pathogenic TRAF2(-/-)TNFalpha(-/-) T cells showed 
      constitutive NFkappaB2p52 activation and produced elevated levels of T-helper 1 and 
      T-helper 17 cytokines. Our results suggest that a regulatory circuit consisting 
      of TRAF2-NFkappaB-induced kinase-NFkappaB2p52 is essential for the proper control of 
      effector T-cell polarization and that loss of T-cell TRAF2 function induces 
      constitutive NFkappaB2p52 activity that drives fatal autoimmune inflammation 
      independently of TNFalpha signaling. The involvement of this regulatory circuit in 
      controlling autoimmune responses highlights the delicate balance required to 
      avoid paradoxical adverse events when implementing new targeted anti-inflammatory 
      therapies.
FAU - Lin, Wen-Jye
AU  - Lin WJ
AD  - Ontario Cancer Institute, University Health Network, Toronto, ON, Canada M5G 2M9.
FAU - Su, Yu-Wen
AU  - Su YW
FAU - Lu, Yong-Chen
AU  - Lu YC
FAU - Hao, Zhenyue
AU  - Hao Z
FAU - Chio, Iok In Christine
AU  - Chio II
FAU - Chen, Nien-Jung
AU  - Chen NJ
FAU - Brustle, Anne
AU  - Brustle A
FAU - Li, Wanda Y
AU  - Li WY
FAU - Mak, Tak Wah
AU  - Mak TW
LA  - eng
GR  - Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20111031
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Cytokines)
RN  - 0 (NF-kappa B)
RN  - 0 (TNF Receptor-Associated Factor 2)
SB  - IM
MH  - Animals
MH  - *Autoimmunity
MH  - Blotting, Western
MH  - Cytokines/biosynthesis
MH  - Flow Cytometry
MH  - Inflammation/physiopathology
MH  - Mice
MH  - Mice, Knockout
MH  - NF-kappa B/*metabolism
MH  - Polymerase Chain Reaction
MH  - *Signal Transduction
MH  - TNF Receptor-Associated Factor 2/*physiology
PMC - PMC3215017
COIS- The authors declare no conflict of interest.
EDAT- 2011/11/02 06:00
MHDA- 2012/01/26 06:00
PMCR- 2011/10/31
CRDT- 2011/11/02 06:00
PHST- 2011/11/02 06:00 [entrez]
PHST- 2011/11/02 06:00 [pubmed]
PHST- 2012/01/26 06:00 [medline]
PHST- 2011/10/31 00:00 [pmc-release]
AID - 1109427108 [pii]
AID - 201109427 [pii]
AID - 10.1073/pnas.1109427108 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18354-9. doi: 
      10.1073/pnas.1109427108. Epub 2011 Oct 31.