Targeted Disruption of MAIL, a Nuclear IκB Protein, Leads to Severe Atopic Dermatitis-like Disease

Koichi Imaoka,Hiroshi Kitamura,Toshina Oonuma,Masami Morimatsu,Naoki Takeda,Kazuo Todokoro,Akihiro Konno,Takahiko Shiina

doi:10.1074/jbc.m409770200

Abstract

MAIL (molecule-possessing ankyrin repeats induced by lipopolysaccharide) is a nuclear IkappaB protein that is also termed interleukin-1-inducible nuclear ankyrin repeat protein or inhibitor of nuclear factor kappaB (IkappaB) zeta. In this study, we generated Mail-/- mice to investigate the roles of MAIL in whole organisms. Mail-/- mice grew normally until 4-8 weeks after birth, when they began to develop lesions in the skin of the periocular region, face, and neck. MAIL mRNA and protein were constitutively expressed in the skin of wild type controls, especially in the keratinocytes. Serum IgE was higher in Mail-/- mice than in normal. Histopathological analysis indicated that the Mail-/- skin lesions appeared to be atopic dermatitis (AD) eczema with inflammatory cell infiltration. In addition, markedly elevated expression of some chemokines such as thymus and activation-regulated chemokine was detected in the Mail-/- skin lesions, similar to that observed in the skin of patients with AD. In Mail-/- mice, MAIL-deficient keratinocytes might be activated to produce chemokines and induce intraepidermal filtration of inflammatory cells, resulting in the onset of the AD-like disease. These findings suggest that MAIL is an essential molecule for homeostatic regulation of skin immunity. The Mail-/- mouse is a valuable new animal model for research on AD.

Highlights

MAIL is a nuclear I␬B protein that is termed interleukin-1-inducible nuclear ankyrin repeat protein or inhibitor of nuclear factor ␬B (I␬B) ␨
The main findings were: 1) MAIL is constitutively expressed in KCs in normal wild type skin; 2) the lack of MAIL expression in the skin led to severe dermatitis, which appeared to be atopic dermatitis (AD) on histopathological examination; and 3) skin cells of MailϪ/Ϫmice express markedly elevated levels of chemokines associated with AD
The authors reported that the mice developed AD-like skin lesions; the description of the pathophysiological analysis was very limited

Summary

Introduction

MAIL (molecule-possessing ankyrin repeats induced by lipopolysaccharide) is a nuclear I␬B protein that is termed interleukin-1-inducible nuclear ankyrin repeat protein or inhibitor of nuclear factor ␬B (I␬B) ␨. MAIL-deficient mice developed an AD-like disease accompanied by typical cellular infiltrates and chemokine expression patterns in the skin similar to those of patients with AD, providing a possible new mouse model for the study of this common allergic disease.

Results

Conclusion