We found that, in murine podocytes, expression of MCP-1 in response to TNF- was suppressed by indomethacin, but not by ibuprofen. This anti-inflammatory potential was correlated with induction of 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 non-steroidal 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 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 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 TRAF2 and blunted degradation of IB. 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, at least in part, responsible for the suppressive effect of indomethacin.