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PMID: 12526812 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Conversion of proepithelin to epithelins: roles of SLPI and elastase in host defense and wound repair.

Cell ·Vol. 111 ·No. 6 ·2002-12-13 ·Pages 867-78

Zhu J, Nathan C, Jin W, Sim D, Ashcroft GS, Wahl SM, Lacomis L, Erdjument-Bromage H, Tempst P, Wright CD, Ding A

Abstract

Increased leukocyte elastase activity in mice lacking secretory leukocyte protease inhibitor (SLPI) leads to impaired wound healing due to enhanced activity of TGFbeta 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.

MeSH Terms
Amino Acid Sequence Animals Blotting, Western COS Cells Cell Line Cell Membrane/metabolism 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
Chemicals
Fungal Proteins Granulins Growth Inhibitors Intercellular Signaling Peptides and Proteins Interleukin-8 Protein Precursors Proteinase Inhibitory Proteins, Secretory Proteins Recombinant Proteins SLPI protein, human Secretory Leukocyte Peptidase Inhibitor Slpi protein, mouse Protein-Tyrosine Kinases Focal Adhesion Kinase 2 Pancreatic Elastase Oxygen
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Zhu Jing
Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA.
Nathan Carl
Jin Wenwen
Sim Davis
Ashcroft Gillian S
Wahl Sharon M
Lacomis Lynne
Erdjument-Bromage Hediye
Tempst Paul
Wright Clifford D
Ding Aihao
Article Info
Journal
Cell
Abbr.
Cell
ISSN
0092-8674
DOI
10.1016/s0092-8674(02)01141-8
Published
2002-12-13
Pages
867-78
Language
English
Region
United States
NLM ID
0413066
Subset
IM
Grants
NIAID NIH HHS · AI46382 · United States
NIGMS NIH HHS · GM61710 · United States
NCI NIH HHS · P30 CA08748 · United States
External Links
PubMed source DOI: 10.1016/s0092-8674(02)01141-8 View journal details
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