TNFα induces matrix metalloproteinase-9 expression in monocytic cells through ACSL1/JNK/NF- kB signaling pathways

Abstract

Abstract Background Studies have established the association between increased plasma levels of matrix metalloproteinase (MMP)-9 and adipose tissue inflammation. Tumor necrosis factor α (TNFα) was elevated in obesity and is involved in the induction of MMP-9 in monocytic cells. However, the underlying molecular mechanism was incompletely understood. As per our recent report, TNFα mediates inflammatory responses through long-chain acyl-CoA synthetase 1 (ACSL1). Therefore, we further investigated the role of ACSL1 in TNFα-mediated MMP-9 secretion in monocytic cells and macrophages. Methods Monocytic THP-1 cells and macrophages were used to study MMP-9 expression. mRNA and protein levels of MMP-9 were determined by qRT-PCR and ELISA, respectively, and its biological activity was determined by zymography. Signaling pathways were studied using Western blotting, inhibitors, and NF-kB/AP1 reporter cells. Results We found that THP-1 monocytic cells and macrophages displayed increased MMP-9 mRNA expression, as well as biologically active protein secretion after incubation with TNFα. Inhibition of ACSL1 in the cells with triacsin C significantly reduced MMP-9 secretion. However, inhibition of β-oxidation and ceramide biosynthesis was not affected by TNFα-induced MMP-9 production. Using small interfering RNA-mediated knockdown, we further confirmed that TNFα-induced MMP-9 secretion was significantly reduced in ACSL1-deficient cells. Moreover, TNFα-mediated MMP-9 expression was significantly reduced by inhibition of ERK1/ERK2, JNK, and NF-kB signaling pathways. We further observed TNFα-induced phosphorylation of JNK, ERK1/ERK2, and NF-kB. On the other hand, inhibition of ACSL1 reduced TNFα-mediated phosphorylation of JNK, c-Jun, ERK1/2, and NF-kB in THP-1 monocytic cells. In addition, increased NF-κB/AP-1 activity was inhibited in triacsin C-treated cells. Conclusion Altogether, our findings suggest that ACSL1/JNK/ ERK/NF-kB axis plays an important role in the regulation of MMP-9 induced by TNFα in monocytic THP-1 cells and macrophages.