Abstract
Epithelial keratinocyte proliferation is an essential element of wound repair, and abnormal epithelial proliferation is an intrinsic element in the skin disorder psoriasis. The factors that trigger epithelial proliferation in these inflammatory processes are incompletely understood. Here we have shown that regenerating islet-derived protein 3-alpha (REG3A) is highly expressed in keratinocytes during psoriasis and wound repair and in imiquimod-induced psoriatic skin lesions. The expression of REG3A by keratinocytes is induced by interleukin-17 (IL-17) via activation of keratinocyte-encoded IL-17 receptor A (IL-17RA) and feeds back on keratinocytes to inhibit terminal differentiation and increase cell proliferation by binding to exostosin-like 3 (EXTL3) followed by activation of phosphatidylinositol 3 kinase (PI3K) and the kinase AKT. These findings reveal that REG3A, a secreted intestinal antimicrobial protein, can promote skin keratinocyte proliferation and can be induced by IL-17. This observation suggests that REG3A may mediate the epidermal hyperproliferation observed in normal wound repair and in psoriasis.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / metabolism*
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism*
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Cell Differentiation* / genetics
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Cell Proliferation
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Epidermis / drug effects
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Epidermis / injuries
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Epidermis / metabolism
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Gene Expression / drug effects
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Humans
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Interleukin-17 / pharmacology
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Keratinocytes / cytology*
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Keratinocytes / drug effects
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Keratinocytes / metabolism*
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Lectins, C-Type / genetics
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Lectins, C-Type / metabolism*
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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N-Acetylglucosaminyltransferases / metabolism
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Pancreatitis-Associated Proteins
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Phosphatidylinositol 3-Kinases / metabolism
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Proteins / genetics
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Proteins / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Psoriasis / immunology
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Psoriasis / metabolism
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Psoriasis / pathology
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Signal Transduction
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Skin / drug effects
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Skin / injuries*
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Skin / metabolism*
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Wound Healing / genetics
Substances
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Antigens, Neoplasm
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Biomarkers, Tumor
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EXTL3 protein, human
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Interleukin-17
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Lectins, C-Type
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Pancreatitis-Associated Proteins
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Proteins
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REG3A protein, human
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REG3G protein, human
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Reg3a protein, mouse
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N-Acetylglucosaminyltransferases
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt