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Abbreviations: AP-1, activating factor-1; BCIP, bromochloroindolyl phosphate; 15d-PGJ2, 15-Deoxy-12,14 -Prostaglandin J2; HODE, hydroxyoctadecadienoic acid; LXR, liver X receptor; MMP-9, matrix metalloproteinase-9; NBT, nitro blue tetrazolium; NF-κB, nuclear factor-kappa B; ox-LDL, oxidized low-density lipoprotein; PGF2α , prostaglandin F2α ; PPAR-γ, peroxisome proliferator-activated factor receptor-γ; RXR, retinoid X receptor; STAT, signal transducers and activators of transcription; TZD, thiazolidinedione

Heat shock protein 70 (Hsp70) release and its effects on pro-inflammatory cytokine production have been controversial. In this study, we investigated whether Hsp70 could be released from monocytes and activates matrix metalloproteinase-9 (MMP-9) gene expression. Hsp70 overexpression in human monocytic cell line U937 was found to increase PMAinduced MMP-9 expression and enhance cell motility. Hsp70 cDNA transfectants released Hsp70 protein into culture supernatants, and a part of released Hsp70 subsequently was bound to the surface of U937 cells. Addition of culture medium containing the extracelluar Hsp70 led to an increase not only in proMMP-9 secretion, but also the invasiveness of U937 cells through Matrigel or human umbilical vascular endothelial cells (HUVEC) in vitro. Immunodepletion of Hsp70 abolished its effect on MMP-9 expression. The released Hsp70 activated nuclear factor kappa B (NF-κB) and activating protein-1 (AP-1), which led to the activation of MMP-9 transcription. Taken together, these results suggest that extracellular Hsp70 induces the expression of MMP-9 gene through activation of NF-κB and AP-1.