Biochemical Analysis of Matrix Metalloproteinase Activation of Chemokines CCL15 and CCL23 and Increased Glycosaminoglycan Binding of CCL16*
| Autor: | Josefine Maier, Antoine Dufour, Christopher M. Overall, Amanda E. Starr |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Leukocyte migration
Proteases Immunology Molecular Sequence Data CCL1 Biology Matrix metalloproteinase Ligands Biochemistry Monocytes Cell Line Substrate Specificity 03 medical and health sciences 0302 clinical medicine Mass Spectrometry (MS) Calcium flux Synovial Fluid Humans Amino Acid Sequence Molecular Biology Macrophage inflammatory protein 030304 developmental biology Glycosaminoglycans Inflammation 0303 health sciences Glycosaminoglycan binding Matrix Metalloproteinase (MMP) Heparin Arthritis Chemotaxis Macrophages Cell Biology Macrophage Inflammatory Proteins Molecular biology Matrix Metalloproteinases 3. Good health Protease Enzyme Activation Kinetics 030220 oncology & carcinogenesis Chemokines CC Calcium Chemokines Protein Binding |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X 0021-9258 |
| Popis: | Background: Proteases responsible for a CCL15-(25–92) product have not been elucidated. Results: All 14 CC monocyte chemoattractants, including CCL15, are processed by multiple MMPs. Conclusion: MMP-processing of CCL15, CCL23, and CCL16 functional activity is altered by MMP processing. Significance: This is the first study showing MMPs can activate CC chemokines and hence monoycte chemoattraction with potential to propagate inflammation. Leukocyte migration and activation is orchestrated by chemokines, the cleavage of which modulates their activity and glycosaminoglycan binding and thus their roles in inflammation and immunity. Early research identified proteolysis as a means of both activating or inactivating CXC chemokines and inactivating CC chemokines. Recent evidence has shown activating cleavages of the monocyte chemoattractants CCL15 and CCL23 by incubation with synovial fluid, although the responsible proteases could not be identified. Herein we show that CCL15 is processed in human synovial fluid by matrix metalloproteinases (MMPs) and serine proteases. Furthermore, a family-wide investigation of MMP processing of all 14 monocyte-directed CC chemokines revealed that each is precisely cleaved by one or more MMPs. By MALDI-TOF-MS, 149 cleavage sites were sequenced including the first reported instance of CCL1, CCL16, and CCL17 proteolysis. Full-length CCL15-(1–92) and CCL23-(1–99) were cleaved within their unique 31 and 32-amino acid residue extended amino termini, respectively. Unlike other CCL chemokines that lose activity and become receptor antagonists upon MMP cleavage, the prominent MMP-processed products CCL15-(25–92, 28–92) and CCL23-(26–99) are stronger agonists in calcium flux and Transwell CC receptor transfectant and monocytic THP-1 migration assays. MMP processing of CCL16-(1–97) in its extended carboxyl terminus yields two products, CCL16-(8–77) and CCL16-(8–85), with both showing unexpected enhanced glycosaminoglycan binding. Hence, our study reveals for the first time that MMPs activate the long amino-terminal chemokines CCL15 and CCL23 to potent forms that have potential to increase monocyte recruitment during inflammation. |
| Databáze: | OpenAIRE |
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