IL-6 amplifier, NF-κB-triggered positive feedback for IL-6 signaling, in grafts is involved in allogeneic rejection responses

Jihye Lee, Tomoyuki Nakagiri, Takahiro Oto, Masaya Harada, Eiichi Morii, Yasushi Shintani, Masayoshi Inoue, Yoichiro Iwakura, Shinichiro Miyoshi, Meinoshin Okumura, Toshio Hirano, Masaaki Murakami

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35 Citations (Scopus)

Abstract

The IL-6-amplifier first was discovered as a synergistic activation mechanism for NF-κB/STAT3 in type 1 collagen + cells. This process is marked by the hyperinduction of chemokines and subsequent local inflammation that leads to autoimmune diseases. In this study, we show that IL-6 amplifier activation in grafts plays important roles in allogeneic graft rejection by using a tracheal heterotopic transplantation model that includes bronchiolitis obliterans, a pathological marker for chronic rejection. IL-6, epidermal growth factor, and IFN-γ all stimulate IL-6 amplifier activation, whereas CCL2, a chemotactic factor for Th1 cells, was one of the amplifier's main targets. Interestingly, IFN-γ hyperinduced CCL2 in type 1 collagen + cells via the IL-6 amplifier at least in vitro. In addition, we detected IL-6, CCL2, phospho-STAT3, and phospho-NF-κB in epithelial type 1 collagen + cells of allogeneic tracheal grafts. These results show that IL-6 amplifier activation in grafts plays a critical role for graft rejection responses after allogeneic transplantation, including chronic rejection. From these results, we consider whether the IL-6 amplifier in grafts might be a valuable therapeutic target for the prevention of transplant rejection, including chronic rejection.

Original languageEnglish
Pages (from-to)1928-1936
Number of pages9
JournalJournal of Immunology
Volume189
Issue number4
DOIs
Publication statusPublished - Aug 15 2012

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Lee, J., Nakagiri, T., Oto, T., Harada, M., Morii, E., Shintani, Y., Inoue, M., Iwakura, Y., Miyoshi, S., Okumura, M., Hirano, T., & Murakami, M. (2012). IL-6 amplifier, NF-κB-triggered positive feedback for IL-6 signaling, in grafts is involved in allogeneic rejection responses. Journal of Immunology, 189(4), 1928-1936. https://doi.org/10.4049/jimmunol.1103613