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Suppression of NF-B by Cyclosporin A and Tacrolimus (FK506) via Induction of the C/EBP Family: Implication for Unfolded Protein Response¹

Shuqi Du^2,,, Nobuhiko Hiramatsu^2,*, Kunihiro Hayakawa^*, Ayumi Kasai^*, Maro Okamura^*, Tao Huang^*, Jian Yao^*, Masayuki Takeda, Isao Araki, Norifumi Sawada^*,, Adrienne W. Paton, James C. Paton and Masanori Kitamura^3,*

^* Department of Molecular Signaling and Department of Urology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan; School of Molecular and Biomedical Science, University of Adelaide, South Australia, Australia; and Department of Urology, First Affiliated Hospital of China Medical University, Shenyang, China

Immunosuppressive agents cyclosporin A (CsA) and tacrolimus (FK506) inhibit cytokine production by activated lymphocytes through interfering with calcineurin. However, little is known about their effects on the function of nonlymphoid cells. We found that, in renal tubular cells, induction of MCP-1 by inflammatory cytokines was blunted by CsA and FK506. This suppression was correlated with induction of unfolded protein response (UPR) evidenced by endogenous and exogenous indicators. The induction of UPR by these agents was reversible and observed generally in other nonimmune cells. Furthermore, administration with CsA in reporter mice caused rapid, systemic induction of UPR in vivo. In TNF--treated cells, suppression of MCP-1 by CsA or FK506 was associated with blunted responses of NF-B, the crucial regulator of MCP-1. The suppression of NF-B was reproduced by other inducers of UPR including AB₅ subtilase cytotoxin, tunicamycin, thapsigargin, and A23187. CsA and FK506, as well as other UPR inducers, caused up-regulation of C/EBP family members, especially C/EBPβ and CHOP (C/EBP homologous protein), and overexpression of either C/EBPβ or CHOP significantly attenuated TNF--triggered NF-B activation. Furthermore, down-regulation of C/EBPβ by small interfering RNA substantially reversed the suppressive effect of CsA on TNF--induced MCP-1 expression. These results suggested that CsA and FK506 confer insensitiveness to TNF- on resident cells through UPR-dependent induction of the C/EBP family members.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported, in part, by Grant-in-Aids for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (nos. 16390243, 17651026, and 19651024 to M.K.).

² S.D. and N.H. equally contributed to this work.

³ Address correspondence and reprint requests to Dr. Masanori Kitamura, Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato 1110, Chuo, Yamanashi 409-3898, Japan. E-mail address: masanori{at}yamanashi.ac.jp

⁴ Abbreviations used in this paper: CsA, cyclosporin A; FK506, tacrolimus; FKBP12, FK506-binding protein 12; HSP, heat shock protein; UPR, unfolded protein response; CHOP, C/EBP homologous protein; SubAB, AB₅ subtilase cytotoxin; GRP78, 78-kDa glucose-regulated protein; siRNA, small interfering RNA; SEAP, secreted alkaline phosphatase; ER, endoplasmic reticulum; ES-TRAP, ER stress-responsive alkaline phosphatase; IKK, IB kinase; TRADD, TNFR1-associated death domain; RIP, receptor-interacting protein; TRAF2, TNFR-associated factor 2; bZIP, basic leucine zipper; PPI, peptidyl-prolyl cis/trans isomerase; IRE1, inositol-requiring ER-to-nucleus signal kinase 1.

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