Convergence of Itch-induced ubiquitination with MEKK1-JNK signaling in Th2 tolerance and airway inflammation
K. Venuprasad, … , Michael Karin, Yun-Cai Liu
K. Venuprasad, … , Michael Karin, Yun-Cai Liu
Published April 3, 2006
Citation Information: J Clin Invest. 2006;116(4):1117-1126. https://doi.org/10.1172/JCI26858.
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Research Article Immunology

Convergence of Itch-induced ubiquitination with MEKK1-JNK signaling in Th2 tolerance and airway inflammation

Abstract

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.

Authors

K. Venuprasad, Chris Elly, Min Gao, Shahram Salek-Ardakani, Yohsuke Harada, Jun-Li Luo, Chun Yang, Michael Croft, Kazushi Inoue, Michael Karin, Yun-Cai Liu

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Figure 6

Suppression of JunB expression reverses anergy induction in Itch–/– T cells.

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Suppression of JunB expression reverses anergy induction in...
(A) Naive CD4+ T cells were isolated from Itch–/– mice using MACS beads, and the cells were cultured under Th2-differentiating conditions for 2 days. The cells were then infected with retrovirus derived from pSuper interfering RNA (RNAi) empty vector or pSuper JunB RNAi. Aliquots of cell lysates were immunoblotted with anti-JunB. The same membrane was reprobed with anti-actin. (B and C) The cells were then incubated with ionomycin for 16 hours, washed, and restimulated with anti-CD3 and anti-CD28. The cell proliferation (B) and IL-4 production (C) were measured.