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.