Convergence of Itch-induced ubiquitination with MEKK1-JNK signaling in Th2 tolerance and airway inflammation.
The immune system is capable of mounting robust responses against invading pathogens but refrains from attacking self. Many studies have focused on tolerance induction of Th1 cells, whose failure results in development of autoimmune diseases. However, the molecular mechanisms governing tolerance induction in Th2 cells and its relation to allergic responses remain unclear. Here we used both in vivo and in vitro protocols to demonstrate that Th2 cells either containing a mitogen and extracellular kinase kinase 1 (MEKK1) mutant or lacking JNK1 or the E3 ubiquitin ligase Itch cannot be tolerized. In a mouse allergic model, injection of high-dose tolerizing antigen failed to block the development of airway inflammation in Itch-/- mice. This study suggests that MEKK1-JNK signaling regulates Itch E3 ligase-mediated tolerogenic process in Th2 cells. These findings have therapeutic implications for allergic diseases.
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA.
K
K
Venuprasad
Chris
C
Elly
Min
M
Gao
Shahram
S
Salek-Ardakani
Yohsuke
Y
Harada
Jun-Li
JL
Luo
Chun
C
Yang
Michael
M
Croft
Kazushi
K
Inoue
Michael
M
Karin
Yun-Cai
YC
Liu
D000818:Animals; D001991:Bronchitis / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000276:immunology*; D005434:Flow Cytometry; D007108:Immune Tolerance; D048670:MAP Kinase Kinase 4 / Q000276:immunology / Q000378:metabolism*; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016759:Oncogene Protein p65(gag-jun) / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
D016759:Oncogene Protein p65(gag-jun); C471637:Itch protein, mouse; D044767:Ubiquitin-Protein Ligases; D048728:MAP Kinase Kinase Kinase 1; D048670:MAP Kinase Kinase 4; D044764:Ubiquitin-Activating Enzymes