Suppression of NF-kappaB by cyclosporin a and tacrolimus (FK506) via induction of the C/EBP family: implication for unfolded protein response.
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-alpha-treated cells, suppression of MCP-1 by CsA or FK506 was associated with blunted responses of NF-kappaB, the crucial regulator of MCP-1. The suppression of NF-kappaB was reproduced by other inducers of UPR including AB(5) 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/EBPbeta and CHOP (C/EBP homologous protein), and overexpression of either C/EBPbeta or CHOP significantly attenuated TNF-alpha-triggered NF-kappaB activation. Furthermore, down-regulation of C/EBPbeta by small interfering RNA substantially reversed the suppressive effect of CsA on TNF-alpha-induced MCP-1 expression. These results suggested that CsA and FK506 confer insensitiveness to TNF-alpha on resident cells through UPR-dependent induction of the C/EBP family members.
Du
Shuqi
S
Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan .
Hiramatsu
Nobuhiko
N
Hayakawa
Kunihiro
K
Kasai
Ayumi
A
Okamura
Maro
M
Huang
Tao
T
Yao
Jian
J
Takeda
Masayuki
M
Araki
Isao
I
Sawada
Norifumi
N
Paton
Adrienne W
AW
Paton
James C
JC
Kitamura
Masanori
M
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D002460:Cell Line; D018932:Chemokine CCL2; D016572:Cyclosporine / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007684:Kidney Tubules / Q000166:cytology; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017510:Protein Folding; D051381:Rats; D013552:Swine; D016559:Tacrolimus / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha
D022762:CCAAT-Enhancer-Binding Proteins; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D016572:Cyclosporine; D016559:Tacrolimus