Suppression of cytokine response by GATA inhibitor K-7174 via unfolded protein response.
K-7174, a GATA-specific inhibitor, is a putative anti-inflammatory agent that attenuates effects of inflammatory cytokines in certain cell types. However, molecular mechanisms involved have not been elucidated. We found that, in glomerular podocytes, induction of monocyte chemoattractant protein 1 (MCP-1) and inducible nitric oxide synthase (iNOS) by TNF-alpha was abrogated by K-7174. It was correlated with unexpected induction of unfolded protein response (UPR) evidenced by: (1) induction of endogenous indicators 78 kDa glucose-regulated protein and CCAAT/enhancer-binding protein-homologous protein, and (2) suppression of an exogenous indicator, endoplasmic reticulum stress-repressive alkaline phosphatase. In podocytes, induction of UPR by either tunicamycin, thapsigargin, A23187 or AB5 subtilase cytotoxin completely reproduced the suppressive effect of K-7174. Furthermore, K-7174-elicited UPR abrogated induction of MCP-1 and iNOS not only by TNF-alpha but also by medium conditioned by activated macrophages. These results suggested a novel, UPR-dependent mechanism underlying the anti-inflammatory potential of K-7174.
Takano
Yosuke
Y
Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato 1110, Chuo, Yamanashi 409-3898, Japan.
Hiramatsu
Nobuhiko
N
Okamura
Maro
M
Hayakawa
Kunihiro
K
Shimada
Tsuyoshi
T
Kasai
Ayumi
A
Yokouchi
Makiko
M
Shitamura
Akihiro
A
Yao
Jian
J
Paton
Adrienne W
AW
Paton
James C
JC
Kitamura
Masanori
M
D000818:Animals; D000840:Anisoles / Q000008:administration & dosage*; D001381:Azepines / Q000008:administration & dosage*; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum; D050980:GATA Transcription Factors / Q000378:metabolism*; D051379:Mice; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism*; D011489:Protein Denaturation / Q000187:drug effects; D017510:Protein Folding
D000840:Anisoles; D001381:Azepines; D016207:Cytokines; D050980:GATA Transcription Factors; C410337:K 7174