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 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.
Zhu
Jing
J
Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA.
Nathan
Carl
C
Jin
Wenwen
W
Sim
Davis
D
Ashcroft
Gillian S
GS
Wahl
Sharon M
SM
Lacomis
Lynne
L
Erdjument-Bromage
Hediye
H
Tempst
Paul
P
Wright
Clifford D
CD
Ding
Aihao
A
D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000378:metabolism; D051418:Focal Adhesion Kinase 2; D005656:Fungal Proteins / Q000378:metabolism; D000077155:Granulins; D006131:Growth Inhibitors / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D008954:Models, Biological; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010196:Pancreatic Elastase / Q000502:physiology*; D010766:Phosphorylation; D011233:Precipitin Tests; D011498:Protein Precursors / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D053481:Secretory Leukocyte Peptidase Inhibitor; D014162:Transfection; D020798:Two-Hybrid System Techniques; D014945:Wound Healing
D005656:Fungal Proteins; D000077155:Granulins; D006131:Growth Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D011498:Protein Precursors; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D011994:Recombinant Proteins; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; C506815:Slpi protein, mouse; D011505:Protein-Tyrosine Kinases; D051418:Focal Adhesion Kinase 2; D010196:Pancreatic Elastase; D010100:Oxygen