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

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.

Mechanisms of Silk-Derived Protein (SDP) Hydrolysate Stability within Aqueous Formulation and In Vitro Assessment of NF-kB Inflammatory Pathway Inhibition

“…Previous research has demonstrated that broin affects both NF-kB driven in ammation and wound healing [5,6,22]; therefore, the propensity for SDP to activate the canonical NF-kB signaling pathway was investigated as a baseline for bioactivity. The nuclear transcription factor p65 is part of the NF-kB complex, which translocates into the cell nucleus upon activation to facilitate pro-in ammatory gene expression, including TNF-α and MMP-9 [34]. The NF-kB pathway was stimulated within HCLE cultures using TNF-α, and then treated with increasing doses of SDP.…”

Silk-Derived Protein-4 (SDP-4) versus a novel sodium acetate vehicle in the treatment of patients with moderate to severe dry eye disease: a randomized, dual cohort, controlled trial

“…Such proin ammatory factors collectively degrade the ocular surface through disruption of the mucin protein coating, which provides the foundation for a stable and hydrating protective tear lm (5,6). In ammatory mediators regulated by NF-κB, such as matrix metalloprotease (MMP)-9, tumor necrosis factor alpha (TNF-α), and interleukin (IL)-8, have been found at high concentrations in the tear uid in patients exhibiting severe DED (7)(8)(9). Topical administration of MMP-9 to DED-MMP-9-knockout mice subjected to dry eye via cholinergic blockade signi cantly increases corneal epithelial permeability, implicating MMP-9 in increased corneal epithelial disruption and damage (10).…”