Abstract
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 PMA-induced 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-kappaB) 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-KappaB and AP-1.
Highlights
Most organisms express constitutive and stressinduced forms of Heat shock protein 70 (Hsp70), which are involved in protein folding, translocation, oligomer dissociation, and prevention of protein aggregation
We investigated by Northern blot analysis whether the stimulatory effect of Hsp70 on proMMP-9 secretion resulted from increased matrix metalloproteinase-9 (MMP-9) mRNA expression
Lower panel, the result indicates that U937 cells expressed the 2.3 kb mRNA species for MMP-9, and Hsp70 transfectants induced more MMP-9 mRNA expression than mock transfectants. These results demonstrate that overexpression of Hsp70 increases MMP-9 mRNA expression in monocytes/macrophages
Summary
Most organisms express constitutive and stressinduced forms of Hsp, which are involved in protein folding, translocation, oligomer dissociation, and prevention of protein aggregation. Plasma concentrations of Hsp were shown to be associated significantly with postoperative infection (Kimura et al, 2004). These results suggest that Hsp can be released into extracellular spaces and may be involved in postoperative inflammatory responses and in the pathogenesis of postoperative organ dysfunction. Some results suggest that the reported cytokine function of Hsp may have resulted from contamination by lipopolyscharride (LPS) (Bausinger et al, 2002; Gao and Tsan, 2003a, b, c; Tsan and Gao, 2004a, b c; Wang et al, 2005). The question of whether the released Hsp has any cytokine effect still remains elusive
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