Degradation of Interleukin 1β by Matrix Metalloproteinases

Abstract

Matrix metalloproteinases (MMPs) and interleukin 1 (IL-1) are implicated in inflammation and tissue destruction, where IL-1 is a potent stimulator of connective tissue cells to produce the extracellular matrix-degrading MMPs. Here, we report that IL-1␤, but not IL-1␣, is degraded by MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin 1), and MMP-9 (gelatinase B). This degradation was effectively blocked by tissue inhibitor of metalloproteinases (TIMP)-1. When IL-1␤ was treated with MMPs it lost the ability to enhance the synthesis of prostaglandin E 2 and pro-MMP-3 in human fibroblasts. The primary cleavage site of IL-1␤ by MMP-2 was identified at the Glu 25 -Leu 26 bond. These results suggest that IL-1␤ stimulates connective tissue cells to produce MMPs, but activated MMPs in turn negatively regulate the activity of IL-1␤. Matrix metalloproteinases (MMPs),1 also called matrixins, degrade extracellular matrix macromolecules and play important roles in many biological processes such as morphogenesis, ovulation, embryo implantation, cell migration, tissue involution, angiogenesis, and wound healing (1-3). In excess, they participate in the destruction of the tissue associated with many connective tissue diseases such as arthritis, periodentitis, nephritis, and tissue ulcerations and with tumor cell invasion and metastasis (1-3). The importance of matrixins in both physiological and pathological catabolism of extracellular matrix macromolecules has been emphasized because little MMP activities can be detected in normal steady state tissue, but the synthesis of many MMPs is transcriptionally regulated by inflammatory cytokines, hormones, growth factors, and cellular transformation (1-3). For example, high levels of MMP-1 (interstitial collagenase, EC 3.4.24.7), MMP-3 (stromelysin 1, EC 3.4.24.17), and MMP-9 (gelatinase B, EC 3.4.24.35) are found in synovial tissues and fluids from patients with rheumatoid arthritis (4 -6). It is generally accepted that an elevated level of interleukin 1 (IL-1) is one of the key mediators that greatly enhances the biosynthesis and secretion of precursors of these MMPs (pro-MMPs) and prostaglandin E 2 from mesenchymal cells at inflammatory sites (1).IL-1 is secreted from activated macrophages and a variety of other cell types and elicits many other biological responses such as thymocyte proliferation, fever production, wound healing, and tissue resorption (see Ref. 7 for review). The promotion of wound healing and tissue degradation is considered to be in part due to the production of MMPs by cells stimulated with IL-1. The suppression of IL-1 activity is, therefore, thought to be an effective step to control inflammatory responses. In this regard, a large number of studies have focused on the regulation of IL-1 synthesis, processing of the IL-1 precursor, and the receptor antagonist (7). However, little is known about the catabolism of the mature form of IL-1.In this communication, we report that MMP-1, MMP-2 (gelatinase A, EC 3.4.24.24), MMP-3, and MMP-9 secre...

Stimulation of Matrix Metalloproteinase-9 Expression in Human Fibrosarcoma Cells by Synthetic Matrix Metalloproteinase Inhibitors

“…7). A similar stimulation of IL-1β secretion by synthetic MMPIs has been previously documented by others [27,58,59] and results most probably from the inhibition of an MMP-mediated IL-1β degradation [60]. In order to assess whether this elevated IL-1β concentration could mediate MMP-9 overexpression, HT1080 cells, treated or not with GI129471 (1 µM), were supplemented with increasing concentrations of recombinant human IL-1β (0-5 ng/ml) and 48-h conditioned media were analyzed by gelatin zymography.…”

“…Moreover, the MMPImediated upregulation of MMP-9 clearly differs from the well-characterized induction observed in the presence of TPA in that: (1) it requires a longer incubation period and (2) it is cell type specific, suggesting the involvement of distinct mediators and/or signaling pathways. Among the numerous factors known to regulate MMP-9 expression, we selected IL-1β and TNF-α for further investigation because their bioactivities have previously been reported to be modulated by MMPs or MMP-like proteinases [60,64]. However, our data do not reveal any implication for these two cytokines in MMP-9 upregulation.…”

Lack of matrix metalloproteinase-9 worsens ventilator-induced lung injury

“…In opposite, lack of MMP-2 is related to the sequestration of neutrophils inside the interstitium, without invasion of the air spaces (9). It is known that MMP-9 can cleave different cytoand chemokines, like IL-1␤ (23). By these effects, MMPs can modulate cell migration (18).…”

The Role of Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9 in Antibody-Induced Arthritis

“…Because MMP-2 activity is controlled by its activation from proenzyme (1)(2)(3)21) and endogenous inhibitors (1)(2)(3), this enzyme may function in a specific region. Recently, a number of non-matrix MMP substrates that potently influence cellular functions (13), such as cytokines (10), growth factor receptor (12), and chemokine (11), have been identified. The major role of MMP-2 in AbIA may be to degrade inflammatory factors or to activate antiinflammatory factors, although the substrates have not been determined.…”