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Department of Medicine, Royal Free and University College Medical School, University College London, Jules Thorn Institute, Middlesex Hospital, London, United Kingdom
Proteasome inhibitors, the well-known inhibitors of NF-
B, are
recently considered therapeutic agents for inflammation. However, the
anti-inflammatory properties of these agents have not been fully
evaluated. In this report we describe a novel effect of proteasome
inhibitors on the expression of monocyte chemoattractant protein 1
(MCP-1) in mesangial cells. We found that proteasome inhibitor MG132
dose-dependently induced expression of MCP-1 at the transcriptional
level. The stimulatory effect was similarly observed with other
proteasome inhibitors (proteasome inhibitor 1 and lactacystin) and in
other cell types (NRK fibroblasts). The 5'-flanking region of the
MCP-1 gene contains multiple AP-1 sites. To explore the
mechanisms involved, we examined the effects of proteasome inhibition
on the AP-1 pathway. Northern blot analysis showed that MG132 rapidly
induced the expression of c-jun, but not
c-fos. Immunoblot analysis showed that MG132 prevented
degradation of c-Jun protein. Kinase assay revealed that c-Jun
N-terminal kinase (JNK) was rapidly activated by MG132. Consistent with
these results, a reporter assay showed that AP-1 activity was
up-regulated after treatment with MG132. Curcumin, a pharmacological
inhibitor of the JNK-AP-1 pathway, abrogated the induction of MCP-1 by
MG132. Similarly, stable transfection with a dominant-negative mutant
of c-Jun attenuated both MG132-induced activation of AP-1 and
expression of MCP-1. The transcriptional activation by proteasome
inhibitors was observed not only in MCP-1, but also in other
AP-1-dependent genes, including stromelysin and mitogen-activated
protein kinase phosphatase 1. These data revealed that proteasome
inhibition triggered the expression of MCP-1 and other genes via the
multistep induction of the JNK-c-Jun/AP-1
pathway.
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