Conversion of Proepithelin to Epithelins: Roles of SLPI and Elastase in Host Defense and Wound Repair

Increased leukocyte elastase activity in mice lacking secretory leukocyte protease inhibitor (SLPI) leads to impaired wound healing due to enhanced activity of TGFβ and perhaps additional mechanisms. Proepithelin (PEPI), an epithelial growth factor, can be converted to epithelins (EPIs) in vivo by u...

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Bibliographic Details
Published in:Cell 2002-12, Vol.111 (6), p.867-878
Main Authors: Zhu, Jing, Nathan, Carl, Jin, Wenwen, Sim, Davis, Ashcroft, Gillian S., Wahl, Sharon M., Lacomis, Lynne, Erdjument-Bromage, Hediye, Tempst, Paul, Wright, Clifford D., Ding, Aihao
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Blotting, Western
Cell Line
Cell Membrane - metabolism
COS Cells
Dose-Response Relationship, Drug
Epithelial Cells - metabolism
Focal Adhesion Kinase 2
Fungal Proteins - metabolism
Granulins
Growth Inhibitors - metabolism
Humans
Intercellular Signaling Peptides and Proteins - metabolism
Interleukin-8 - metabolism
Leukocytes - immunology
Mice
Mice, Inbred C3H
Models, Biological
Molecular Sequence Data
Neutrophils - metabolism
Oxygen - metabolism
Pancreatic Elastase - physiology
Phosphorylation
Precipitin Tests
Protein Precursors - metabolism
Protein-Tyrosine Kinases - metabolism
Proteinase Inhibitory Proteins, Secretory
Proteins - physiology
Recombinant Proteins - metabolism
Secretory Leukocyte Peptidase Inhibitor
Transfection
Two-Hybrid System Techniques
Wound Healing
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Summary:Increased leukocyte elastase activity in mice lacking secretory leukocyte protease inhibitor (SLPI) leads to impaired wound healing due to enhanced activity of TGFβ and perhaps additional mechanisms. Proepithelin (PEPI), an epithelial growth factor, can be converted to epithelins (EPIs) in vivo by unknown mechanisms with unknown consequences. We found that PEPI and EPIs exert opposing activities. EPIs inhibit the growth of epithelial cells but induce them to secrete the neutrophil attractant IL-8, while PEPI blocks neutrophil activation by tumor necrosis factor, preventing release of oxidants and proteases. SLPI and PEPI form complexes, preventing elastase from converting PEPI to EPIs. Supplying PEPI corrects the wound-healing defect in SLPI null mice. Thus, SLPI/elastase act via PEPI/EPIs to operate a switch at the interface between innate immunity and wound healing.
ISSN:0092-8674
1097-4172
DOI:10.1016/S0092-8674(02)01141-8