Volume 14 Supplement 1

Proceedings of the 8th Global Arthritis Research Network (GARN) Meeting and 1st Bio-Rheumatology International Congress (BRIC)

Open Access

An essential role of IκBζ in the transcriptional program in Th17 development

  • Kazuo Okamoto1,
  • Masatsugu Oh-hora1 and
  • Hiroshi Takayanagi1
Arthritis Research & Therapy201214(Suppl 1):P56

DOI: 10.1186/ar3691

Published: 29 February 2012

IL-17-producing helper T (Th17) cells are a distinct T cell subset characterized by its pathological role in autoimmune diseases. Our group previously showed that Th17 cells function as osteoclastogenic helper T cells in bone destruction associated with inflammation, and that inhibition of Th17 development has the potential of a beneficial impact on bone diseases including rheumatoid arthritis (RA) [1]. It is therefore important to comprehend the molecular mechanism underlying Th17 development in order to develop ideal therapeutic strategies against RA.

IL-6 and TGF-β induce Th17 development, in which the orphan nuclear receptors RORγt and RORα play an indispensable role. We found that the expression of a nuclear IκB family member, IκBζ (encoded by the Nfkbiz gene), was upregulated by the combination of IL-6 and TGF-β, but independently of RORγt [2]. Not only Nfkbiz-/- mice but also Rag2-/- mice transferred with Nfkbiz-/- CD4+ T cells were highly resistant to experimental autoimmune encephalomyelitis, which is a mouse model of multiple sclerosis. Nfkbiz-/- mice were also protected from the activation of osteoclastogenesis and bone destruction in a LPS-induced model of inflammatory bone destruction. When activated in vitro under Th17-polarizing conditions, IL-17 production in Nfkbiz-/- T cells was markedly reduced compared to WT cells. Notably, the expression of RORγt and RORα was comparable between WT and Nfkbiz-/- T cells. Thus, it is unlikely that ROR nuclear receptors function downstream of IκBζ or vice versa.

In the absence of IL-6 and TGF-β, neither the ROR nuclear receptors nor IκBζ induced Th17 development efficiently. However, when IκBζ was overexpressed, either RORγt or RORα strongly induced IL-17 production, even in the absence of exogenous polarizing cytokines. In cooperation with RORγt and RORα, IκBζ enhanced Il17a expression by directly binding to the regulatory region of the Il17a gene. In addition, the expression of Il17f, Il21 and Il23r mRNA was decreased in Nfkbiz-/- T cells. IκBζ also bound to the promoter or the enhancer region of these genes in Th17 cells. Our study demonstrates the essential role of IκBζ in Th17 development, and points to a molecular basis for a novel therapeutic strategy against autoimmune disease.

Authors’ Affiliations

(1)
Department of Cell Signaling, Tokyo Medical and Dental University, Tokyo, Japan. 2GCOE Program, Tokyo, Japan. 3JST, ERATO, Takayanagi Osteonetwork Project

References

  1. Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, Tanaka S, Kodama T, Akira S, Iwakura Y, Cua DJ, Takayanagi H: Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med. 2006, 203: 2673-2682. 10.1084/jem.20061775.PubMed CentralView ArticlePubMedGoogle Scholar
  2. Okamoto K, Iwai Y, Oh-Hora M, Yamamoto M, Morio T, Aoki K, Ohya K, Jetten AM, Akira S, Muta T, Takayanagi H: IκBζ regulates TH17 development by cooperating with ROR nuclear receptors. Nature. 2010, 464: 1381-1385. 10.1038/nature08922.View ArticlePubMedGoogle Scholar

Copyright

© Okamoto et al.; licensee BioMed Central Ltd. 2012

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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