Dipartimento di Oncologia, Università di Torino, Torino, Italy.
PLoS One. 2013 Aug 14;8(8):e71468. doi: 10.1371/journal.pone.0071468. eCollection 2013.
Recently matrix metalloproteinase-9 (MMP-9) and its endogenous inhibitor (tissue inhibitor of metalloproteinase-1, TIMP-1) have been implicated in complicated malaria. In vivo, mice with cerebral malaria (CM) display high levels of both MMP-9 and TIMP-1, and in human patients TIMP-1 serum levels directly correlate with disease severity. In vitro, natural haemozoin (nHZ, malarial pigment) enhances monocyte MMP-9 expression and release. The present study analyses the effects of nHZ on TIMP-1 regulation in human adherent monocytes. nHZ induced TIMP-1 mRNA expression and protein release, and promoted TNF-α, IL-1β, and MIP-1α/CCL3 production. Blocking antibodies or recombinant cytokines abrogated or mimicked nHZ effects on TIMP-1, respectively. p38 MAPK and NF-κB inhibitors blocked all nHZ effects on TIMP-1 and pro-inflammatory molecules. Still, total gelatinolytic activity was enhanced by nHZ despite TIMP-1 induction. Collectively, these data indicate that nHZ induces inflammation-mediated expression and release of human monocyte TIMP-1 through p38 MAPK- and NF-κB-dependent mechanisms. However, TIMP-1 induction is not sufficient to counterbalance nHZ-dependent MMP-9 enhancement. Future investigation on proteinase-independent functions of TIMP-1 (i.e. cell survival promotion and growth/differentiation inhibition) is needed to clarify the role of TIMP-1 in malaria pathogenesis.
最近，基质金属蛋白酶-9（MMP-9）及其内源性抑制剂（金属蛋白酶组织抑制剂-1，TIMP-1）已被认为与复杂疟疾有关。在体内，脑型疟疾（CM）小鼠表现出高水平的 MMP-9 和 TIMP-1，而在人类患者中，TIMP-1 血清水平与疾病严重程度直接相关。在体外，天然血褐素（nHZ，疟色素）增强单核细胞 MMP-9 的表达和释放。本研究分析了 nHZ 对人贴壁单核细胞中 TIMP-1 调节的影响。nHZ 诱导 TIMP-1 mRNA 表达和蛋白释放，并促进 TNF-α、IL-1β 和 MIP-1α/CCL3 的产生。阻断抗体或重组细胞因子分别消除或模拟了 nHZ 对 TIMP-1 的作用。p38 MAPK 和 NF-κB 抑制剂阻断了 nHZ 对 TIMP-1 和促炎分子的所有作用。尽管诱导了 TIMP-1，但 nHZ 仍增强了总明胶酶活性。总之，这些数据表明 nHZ 通过 p38 MAPK 和 NF-κB 依赖性机制诱导炎症介导的人单核细胞 TIMP-1 的表达和释放。然而，TIMP-1 的诱导不足以平衡 nHZ 依赖性 MMP-9 增强。需要进一步研究 TIMP-1 的蛋白酶非依赖性功能（即促进细胞存活和抑制生长/分化），以阐明 TIMP-1 在疟疾发病机制中的作用。
