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 1

Itch deficient mice are resistant to tolerance induction.

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Itch deficient mice are resistant to tolerance induction. (A) WT and Itc...
(A) WT and Itch–/– mice were immunized with OVA in CFA, together with simultaneous injection of soluble OVA or PBS as control. Splenic and lymph node T cells (5 × 105 cells per well) from OVA-immunized Itch+/+ and Itch–/– mice tolerized with OVA or PBS as control were cultured in triplicate with increasing concentrations of OVA peptide plus irradiated splenocytes as APCs. After 48 hours of culture, the cell proliferation was measured by 3H-thymidine incorporation using a scintillation counter. (B and C) The supernatants obtained at 48 hours of culture as in A were collected and were measured for the concentrations of IL-2 (B) and IFN-γ (C) by ELISA. (D–F) Similar experiments were performed, but the mice were immunized with OVA in alum. The concentrations of IL-2 (E) and IL-4 (F) were measured.