Macrophage‐induced expression and release of matrix metalloproteinase 1 and 3 by human preadipocytes is mediated by IL‐1β via activation of MAPK signaling

Abstract

Obesity is associated with a chronic low-grade inflammation and increased macrophage infiltration in adipose tissue. Matrix metalloproteinases (MMPs) are involved in adipose tissue remodeling and inflammatory responses in obesity. This study investigated whether macrophage-derived factors modulate expression and secretion of MMP1 and MMP3 in human preadipocytes. The potential mediators and signaling pathways were also explored. MMP1 and MMP3 were primarily expressed and secreted by preadipocytes and dramatically reduced post-differentiation. Preadipocytes were incubated with RPMI 1640 medium (control) or THP-1 macrophage-conditioned (MC) medium (25% and 100%) for 24 h. MC medium markedly increased mRNA levels of MMP1 (up to 122-fold) and MMP3 (up to 59-fold), as well as protein release of MMP1 (up to 378-fold) and MMP3 (up to 10-fold) in a dose-dependent manner. Treatment with IL-1β or TNFα, the major products of macrophages, also induced MMP1 and MMP3 secretion by preadipocytes. Neutralizing IL-1β abolished the induction of MMP1 and MMP3 in preadipocytes by MC medium while the effects of TNFα neutralization were modest. Furthermore, MC medium or IL-1β led to the phosphorylation of p38, ERK and JNK MAPKs. Inhibition of p38, ERK and JNK reversed the stimulatory effects of MC or IL-1β on MMP1 and MMP3 production. MC medium and IL-1β also activated NF-κB p65 whereas reduced IκBα protein expression in preadipocytes. These results suggest that macrophage accumulation in adipose tissue has a central role in stimulating MMP1 and MMP3 production by preadipocytes, and this is partially mediated by IL-1β via activation of the MAPK and NF-κB signaling pathways.

Stress in Obesity and Associated Metabolic and Cardiovascular Disorders

“…These findings supported the concept that factors in addition to absolute weight burden, such as qualitative features of AT, might be important determinants of CVD [33]. Mechanistically, macrophage-induced expression and release of MMP-1 and MMP-3 by human preadipocytes is mediated by IL-1 β activation [34]. The macrophage-derived apoptosis inhibitor of macrophage (AIM) protein is increased in blood and is incorporated into adipocytes, thereby inducing lipolysis in AT.…”

The effect of lipoaspirates vs. dissected abdominal fat on breast cancer cells in vitro

“…However, we cannot rule out that MCF-7 cells in co-culture with fat tissue may induce an increase of MMP-1 expression in the fat tissue itself. Gao and Bing reported that MMP-1 is expressed and secreted by preadipocytes and to a much lesser extent in mature adipocytes, but can be stimulated by macrophage-conditioned medium in both cells types [49]. …”

PCR array and protein array studies demonstrate that IL-1β(interleukin-1β) stimulates the expression and secretion of multiple cytokines and chemokines in human adipocytes

“…At the level of the adipocyte, IL-1β has recently been shown to inhibit insulin signal transduction, this involving reduced expression of signalling proteins (Gao & Bing, 2011).…”

“…Human recombinant IL-1β (Sigma, UK) was added to the wells at a dose of 2 ng/ml which previous studies have demonstrated provides a maximal, or near-maximal, response in human fat cells (Gao & Bing, 2011). Groups of adipocytes were treated with IL-1β for either 4 h or 24 h (from previous pilot studies, a near maximal response was evident at 4 h); control cells were incubated without IL-1β.…”