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Suppression of cytokine responses by indomethacin in podocytes: a mechanism through induction of unfolded protein response

¹Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan; and ²School of Molecular and Biomedical Science, University of Adelaide, South Australia, Australia

Submitted 19 December 2007 ; accepted in final form 10 September 2008

We found that, in murine podocytes, expression of monocyte chemoattractant protein 1 (MCP-1) in response to TNF- was suppressed by indomethacin but not by ibuprofen. This anti-inflammatory potential was correlated with induction of 78-kDa glucose-regulated protein (GRP78), a marker of unfolded protein response (UPR). Indomethacin, but not ibuprofen, also triggered expression of CHOP, another endogenous indicator of UPR, as well as repression of endoplasmic reticulum stress-responsive alkaline phosphatase, an exogenous indicator of UPR. Like ibuprofen, other nonsteroidal anti-inflammatory drugs including aspirin and sulindac also did not induce UPR, indicating that the induction of UPR by indomethacin was independent of cyclooxygenase inhibition. The induction of UPR by indomethacin was observed similarly in other cells including mesangial cells and tubular epithelial cells. In tumor necrosis factor (TNF)--treated cells, suppression of MCP-1 by indomethacin was inversely correlated with induction of UPR, and other inducers of UPR including tunicamycin, thapsigargin, and A23187 [GenBank] reproduced the suppressive effect. Reporter assays showed that indomethacin as well as thapsigargin attenuated activation of NF-B by TNF-, and it was associated with enhanced degradation of TNF receptor-associated factor 2 (TRAF2) and blunted degradation of IBβ. Subsequent experiments revealed that acute ablation of GRP78 protein by AB₅ subtilase cytotoxin caused reinforcement of MCP-1 induction and NF-B activation by TNF- and that transfection with GRP78 significantly suppressed the cytokine-induced activation of NF-B. These results suggested that indomethacin suppressed the response of podocytes to TNF- via UPR and that UPR-triggered induction of GRP78 and degradation of TRAF2 may be responsible, at least in part, for the suppressive effect of indomethacin.

monocyte chemoattractant protein 1; nuclear factor-B; tumor necrosis factor-; unfolded protein response; 78-kDa glucose-regulated protein

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