Visfatin/PBEF/Nampt induces EMMPRIN and MMP-9 production in macrophages via the NAMPT-MAPK (p38, ERK1/2)-NF-κB signaling pathway

Abstract

Abstract. The adipocytokine visfatin is closely associated with metabolic disorders. This study explored the effects of visfatin on macrophage-induced inflammation in atheroma. The ability of visfatin to enhance extracellular matrix metalloproteinase inducer (EMMPRIN) expression, matrix metalloproteinase-9 (MMP-9) production and enzymatic activity in THP-1 derived macrophages as well as the mechanisms involved were investigated. EMMPRIN and MMP-9 mRNA levels were investigated by RT-PcR. EMMPRIN and MMP-9 protein levels, nuclear factor (NF)-κB -p65 protein levels, peroxisome proliferator-activated receptor γ (PPARγ) protein levels, and mitogen-activated protein kinase (MAPK) phosphorylation were determined by Western blotting. MMP-9 enzymatic activity was assayed by gelatin zymography. Visfatin (50-400 ng/ml) induced EMMPRIN and MMP-9 depending on the dosage used. Visfatin elicited the activation of NF-κB and MAPK (p38, ERK1/2). Exogenous nicotinamide mononucleotide (NMN), the product of nicotinamide phosphoribosyltransferase (NAMPT) activity, mimicked the effects of visfatin on MAPK (p38, ERK1/2)-NF-κB activation and EMMPRIN/MMP-9 induction. Using the p38 inhibitor, SB203580, the ERK1/2 inhibitor Pd98059, the NF-κB inhibitor, pyrrolidine dithiocarbamate and the NAMPT inhibitor FK866, we demonstrated that the visfatin pro-inflammatory action was through the NAMPT-MAPK (p38, ERK1/2)-NF-κB pathway. Furthermore, the visfatin pro-inflammatory action was not prevented by insulin receptor blockade or by a PPARγ agonist. Visfatin did not modulate PPARγ expression. Retinoid X receptor (RXR) agonist suppressed the effects of visfatin on EMMPRIN/MMP-9, NF-κB, but not on MAPK activation. In conclusion, we have demonstrated that visfatin enhances atheroma inflammation through the NAMPT-MAPK (p38, ERK1/2)-NF-κB-EMMPRIN/MMP-9 pathway, a key feature of atherosclerotic diseases linked to metabolic disorders.

Visfatin Induces Inflammation and Insulin Resistance via the NF-κB and STAT3 Signaling Pathways in Hepatocytes

“…Some studies have suggested that visfatin exerted proinflammatory effects, for example, in macrophages [33] and chondrocytes [34]. We evaluated the direct effects of visfatin on proinflammatory cytokine production in hepatocytes and found that visfatin increased production and secretion of the proinflammatory cytokines IL-6, TNF- α , and IL-1 β .…”

The role of visfatin (PBEF/Nampt) in pregnancy complications

“…Romão et al (2014) suggest that the observed increased expression of extracellular matrix metalloproteinase inducer (EMMPRIN) and hyaluronan is linked to an elevated pro-inflammatory response and tissue damage in women with PE, although these authors did not observe clear differences in visfatin levels between normal and pre-eclamptic pregnancies. This should be put into the context of the work by Fan et al (2011), who observed that visfatin at a dose of 50-400 ng/ml induces EMMPRIN and MMP-9…”

NAMPT and NAPRT: Two Metabolic Enzymes With Key Roles in Inflammation

“…Co-stimulatory molecules such as CD40, CD54, and CD80 are also up-regulated in response to eNAMPT exposure, an effect mediated through the activation of PI3-kinase and MAPKs pathways (133). Furthermore, in macrophages NAMPT increases matrix metalloproteinases (MMPs) expression and activity (134). In addition, (iii) eNAMPT has anti-apoptotic effects on immune cells, including neutrophils and macrophages, for example it promotes macrophage survival after induction of endoplasmic reticulum (ER) stress triggering IL-6 secretion and phosphorylation of STAT3 (103).…”