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|Title:||Suppression of cytokine response by GATA inhibitor K-7174 via unfolded protein response|
|Citation:||Biochemical and Biophysical Research Communications, 2007; 360(2):470-475|
|Publisher:||Academic Press Inc|
|Abstract:||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- 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- but also by medium conditioned by activated macrophages. These results suggested a novel, UPR-dependent mechanism underlying the anti-inflammatory potential of K-7174.|
|Keywords:||Cell Line; Endoplasmic Reticulum; Animals; Mice; Anisoles; Azepines; Cytokines; Protein Denaturation; Protein Folding; Dose-Response Relationship, Drug; Podocytes; GATA Transcription Factors|
|Appears in Collections:||Molecular and Biomedical Science publications|
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