MMP Modulation of Cytokines

Matrix metalloproteinases (MMPs) are involved in tissue remodeling and disease processes such as arthritis and cancer.1,2 In addition to modifying extracellular matrix proteins, MMPs are intimately involved in the regulation of the activities of cytokines and cytokine receptors.

IL-1 beta plays a central role in acute and chronic inflammation. MMP-1 (collagenase 1), MMP-2 (gelatinase A), MMP-3 (stromelysin 1), and MMP-9 (gelatinase B), secreted from stimulated connective tissue cells, degrade IL-1 beta into biologically inactive fragments. The primary cleavage site of IL-1 beta by MMP-2 is at the Glu25-Leu26 bond.3 MMP-2, MMP-3, and MMP-9 can also process recombinant IL-1 beta precursor molecule into biologically active forms.4 Thus, MMPs can both up- and down-regulate IL-1 beta activity at sites of acute or chronic inflammation.

The insulin growth factor (IGF)/IGF receptor autocrine loop is mitogenic and regulated, in part, by a family of six IGF binding proteins (IGFBPs). IGFBPs inhibit IGF-induced cell proliferation. IGFBP regulation of IGFs may involve proteolysis. MMP-1, MMP-3, and MMP-9 have been identified as IGFBP proteinases. For example, IGFs and the eicosanoid LTD4 are co-mitogenic for airway smooth muscle (ASM) cells in vitro. MMP-1 activity can produce IGFBP fragments with a low affinity to IGF, thus increasing the bioavailability of IGF for IGF receptors and consequently inducing ASM cellular proliferation. This ASM hyperplasia may contribute to asthmatic pathologies.5 MMP-1 and MMP-3 are the two principle MMPs involved in IGFBP-3 degradation in the serum of pregnant rats.6 The IGF-I/IGF-I R autocrine loop can also sustain cellular proliferation of the prostate adenocarcinoma cell line, DU-145, in serum-free media. IGFBP-3 binding to IGF-I modulates DU-145 cell proliferation by reducing signaling through IGF-I R. IGFBP-3, in turn, is regulated by MMP-9 proteolysis.7

MMPs also modulate the activities of cytokines and their receptors at the cell surface. Cell surface-localized MMP-9 can mediate IGF-I-triggered MCF-7 cell migration.8 It can also proteolytically activate latent TGF-beta and promote tumor cell invasion and angiogenesis.9 Two members of the tumor necrosis family (TNF) family, TNF-alpha and FasL, can be cleaved from the cell surface by MMP-7 (matrilysin) producing bioactive cytokines. For example, cleavage and release of TNF-alpha can initiate macrophage chemotaxis in a model of herniated disc resorption.10 Release of FasL potentiates epithelial cell apoptosis in a model of murine prostate involution.11 A member of the EGF family, heparin-binding EGF (HB-EGF), is cleaved in the juxtamembrane (JM) region by MMP-3 producing soluble and mitogenic HB-EGF.12 The MMP-3 cleavage site in the JM region is at the Glu151-Asn152 bond. The FGF receptor, FGFR1, is cleaved by MMP-2. The soluble receptor can still bind FGF and modulate mitogenic and angiogenic activities.13 MMPs are also associated with cleavage of TGF-alpha and the IL-6 receptor.

MMPs also modify molecules that interact with cytokines and their receptors. For example, decorin, a ubiquitous proteoglycan, forms a complex with TGF-beta and may function as a reservoir of TGF-beta within the extracellular milieu. MMP-2, MMP-3, and MMP-7 can cleave decorin, releasing TGF-beta from the complex.14

No strong pattern has emerged as a cytokine primary peptide sequence cleaved by MMPs. The amino acid sequence 'Glu-Leu-Arg' (ELR), however, identified by a phage display system, is a common denominator of peptide substrates for MMP-7.15 This is a sequence close to the transmembrane domain of FasL and may represent a potential MMP-7 cleavage site.11 The 'ELR' motif is also conserved within the subclass of CXC chemokines. Further investigation is necessary to determine the specificity of MMPs in modulation of cytokines and their receptors.


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