Diverse patterns of cyclooxygenase‐independent metalloproteinase gene regulation in human monocytes

Abstract

BACKGROUND AND PURPOSEMatrix metalloproteinase (MMP) production from monocyte/macrophages is implicated in matrix remodelling and modulation of inflammation. However, knowledge of the patterns and mechanisms of gene regulation of MMPs and their endogenous tissue inhibitors (TIMPs) is fragmentary. MMP up-regulation may be a target for cyclooxygenase (COX) and prostaglandin (PG) receptor inhibition, but the extent and mechanisms of COX-independent MMP up-regulation are unclear.EXPERIMENTAL APPROACHWe studied MMP mRNA expression and selected protein levels in human peripheral blood monocytes before and after adhesion, upon stimulation with bacterial lipopolysaccharide (LPS), PGE2 or forskolin and after culturing with monocyte colony-stimulating factor on plastic or human fibronectin for up to 7 days.KEY RESULTSMonocyte adherence for 2 h transiently up-regulated COX-2, MMP-1, MMP-7 and MMP-10 mRNAs, and persistently up-regulated MMP-2, MMP-9, MMP-14 and MMP-19 mRNAs. LPS, PGE2 or forskolin selectively increased MMP-1, MMP-9, MMP-10, MMP-12 and MMP-14 mRNAs. LPS increased PGE2 production through COX but up-regulated MMP levels independently of COX. Differential dependence on inhibition of p42/44 and p38 mitogen-activated protein kinases, c-jun N-terminal kinase and inhibitor of κB kinase2 paralleled the diverse patterns of MMP stimulation by LPS. Differentiation on plastic increased mRNA levels of MMP-7, MMP-9, MMP-12 and MMP-14 and TIMP-2 and TIMP-3 independently of COX; fibronectin accelerated MMP but not TIMP up-regulation.CONCLUSIONS AND IMPLICATIONSAdhesion, LPS stimulation and maturation of human monocytes lead to selective, COX-independent MMP and TIMP gene regulation, which is a potential target for selective inhibition by signalling kinase inhibitors.

Metalloproteinases promote plaque rupture and myocardial infarction: A persuasive concept waiting for clinical translation

“…Inflammatory activation stimulates MMP-9 expression in human ECs, VSMCs and monocytes [49] through NF-κB, although human macrophages and FCMs express constitutively high levels ( Fig. 1) [20] similar to those seen in rabbits.…”

“…The enzyme is expressed in human ECs, where it can function to activate MMP-1 [27]. MMP-10 is also expressed in human adhered monocytes [49] and classically-activated macrophages [20] and, like MMP-1, is co-localized in human plaques with COX-2 and nuclear NF-κB. An MMP-10, MMP-1 activation cascade is therefore feasible in human plaques and could give rise to plaque instability.…”

Metalloproteinases and Metalloproteinase Inhibitors in Age-Related Diseases

“…Because PGE 2 production is involved in MMP transcription, antagonists at the PGE 2 receptor could also be useful in stabilizing plaques [191,192]. Aspirin and other cyclooxygenase inhibitors also inhibit MMP production by monocytes [78], although cyclooxygenase independent pathways of MMP production may reduce the beneficial impact of these compounds in man [79]. In addition, MMP-1, -3 and -14 are expressed via NF-B, therefore inhibition of this transcription factor might reduce expression of these MMPs [83].…”

“…MMPs are the predominant proteolytic enzymes, thought to participate in weakening the connective tissue matrix in the intima, leading to plaque rupture and acute thrombosis [76,77]. Of note, human peripheral blood monocytes express MMP-8, -9, -14 and -19, TIMP-1 and TIMP-2 constitutively, but activated macrophages and foam cells express high levels of several MMPs, in response to adhesion and pro-inflammatory mediators, either directly, through mitogen-activated protein kinase (MAPK) activation and the NF-B pathway, or indirectly, with prostaglandin E 2 (PGE 2 ) involvement [78,79]. The upregulation of MMP secretion by differentiated macrophages can be stimulated by contact with endothelial cells (ECs) [80] and by adhesion to matrix components, such as collagen [81].…”

Roles of the Cyclooxygenase 2 Matrix Metalloproteinase 1 Pathway in Brain Metastasis of Breast Cancer

“…We have found that COX2 and its product prostaglandin directly up-regulated the expression of MMP1. Previously, the expression of the COX2 gene was reported to be regulated by MMP1 in macrophage (49), indicating that both genes are reciprocally controlled by a potential feedback mechanism. Many aggressive cancer cells express high levels of COX2, and this gene has been shown to affect BBB permeability (50).…”