Increased matriptase zymogen activation in inflammatory skin disorders.
Matriptase, a type 2 transmembrane serine protease, and its inhibitor hepatocyte growth factor activator inhibitor (HAI)-1 are required for normal epidermal barrier function, and matriptase activity is tightly regulated during this process. We therefore hypothesized that this protease system might be deregulated in skin disease. To test this, we examined the level and activation state of matriptase in examples of 23 human skin disorders. We first examined matriptase and HAI-1 protein distribution in normal epidermis. Matriptase was detected at high levels at cell-cell junctions in the basal layer and spinous layers but was present at minimal levels in the granular layer. HAI-1 was distributed in a similar pattern, except that high-level expression was retained in the granular layer. This pattern of expression was retained in most skin disorders. We next examined the distribution of activated matriptase. Although activated matriptase is not detected in normal epidermis, a dramatic increase is seen in keratinocytes at the site of inflammation in 16 different skin diseases. To gain further evidence that activation is associated with inflammatory stimuli, we challenged HaCaT cells with acidic pH or H(2)O(2) and observed matriptase activation. These findings suggest that inflammation-associated reactive oxygen species and tissue acidity may enhance matriptase activation in some skin diseases.
Dept. of Dermatolog, Tri-Service General Hospital, Taipei, Taiwan, R.O.C.
Cheng-Jueng
CJ
Chen
Bai-Yao
BY
Wu
Pai-In
PI
Tsao
Chi-Yung
CY
Chen
Mei-Hsuan
MH
Wu
Yee Lam E
YL
Chan
Herng-Sheng
HS
Lee
Michael D
MD
Johnson
Richard L
RL
Eckert
Ya-Wen
YW
Chen
Fengpai
F
Chou
Jehng-Kang
JK
Wang
Chen-Yong
CY
Lin
D002461:Cell Line, Transformed; D003872:Dermatitis / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D015536:Down-Regulation / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D004817:Epidermis / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000201:enzymology / Q000648:ultrastructure; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism* / Q000502:physiology; D007365:Intercellular Junctions / Q000201:enzymology / Q000378:metabolism / Q000648:ultrastructure; D015603:Keratinocytes / Q000201:enzymology / Q000648:ultrastructure; D053491:Proteinase Inhibitory Proteins, Secretory / Q000378:metabolism / Q000502:physiology; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D015854:Up-Regulation / Q000502:physiology
D018836:Inflammation Mediators; D053491:Proteinase Inhibitory Proteins, Secretory; C109149:SPINT1 protein, human; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; C485596:ST14 protein, human