Activation of the human keratinocyte B1 bradykinin receptor induces expression and secretion of metalloproteases 2 and 9 by transactivation of epidermal growth factor receptor

The B1 bradykinin receptor (BDKRB1) is a component of the kinin cascade localized in the human skin. Some of the effects produced by stimulation of BDKRB1 depend on transactivation of epidermal growth factor receptor (EGFR), but the mechanisms involved in this process have not been clarified yet. Th...

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Bibliographic Details
Published in:Experimental dermatology 2016-09, Vol.25 (9), p.694-700
Main Authors: Matus, Carola E., Ehrenfeld, Pamela, Pavicic, Francisca, González, Carlos B., Concha, Miguel, Bhoola, Kanti D., Burgos, Rafael A., Figueroa, Carlos D.
Format: Article
Language:English
Subjects:
ADAM17 Protein - metabolism
Animals
B1 bradykinin receptor
Cell Line
epidermal growth factor receptor
Kallidin - analogs & derivatives
Kallidin - pharmacology
Keratinocytes - enzymology
Keratinocytes - secretion
Male
MAP Kinase Signaling System
Matrix Metalloproteinase 2 - metabolism
Matrix Metalloproteinase 2 - secretion
Matrix Metalloproteinase 9 - metabolism
Matrix Metalloproteinase 9 - secretion
metalloproteases
Mice, Inbred C57BL
Proto-Oncogene Proteins c-akt - metabolism
Receptor, Bradykinin B1 - agonists
Receptor, Bradykinin B1 - metabolism
Receptor, Epidermal Growth Factor - metabolism
src-Family Kinases - metabolism
transactivation
Transcriptional Activation
wound healing
Wound Healing - drug effects
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Summary:The B1 bradykinin receptor (BDKRB1) is a component of the kinin cascade localized in the human skin. Some of the effects produced by stimulation of BDKRB1 depend on transactivation of epidermal growth factor receptor (EGFR), but the mechanisms involved in this process have not been clarified yet. The primary purpose of this study was to determine the effect of a BDKRB1 agonist on wound healing in a mouse model and the migration and secretion of metalloproteases 2 and 9 from human HaCaT keratinocytes and delineate the signalling pathways that triggered their secretion. Although stimulation of BDKRB1 induces weak chemotactic migration of keratinocytes and wound closure in an in vitro scratch‐wound assay, the BDKRB1 agonist improved wound closure in a mouse model. BDKRB1 stimulation triggers synthesis and secretion of both metalloproteases, effects that depend on the activity of EGFR and subsequent phosphorylation of ERK1/2 and p38 mitogen‐activated protein kinases and PI3K/Akt. In the mouse model, immunoreactivity for both gelatinases was concentrated around wound borders. EGFR transactivation by BDKRB1 agonist involves Src kinases family and ADAM17. In addition to extracellular matrix degradation, metalloproteases 2 and 9 regulate cell migration and differentiation, cell functions that are associated with the role of BDKRB1 in keratinocyte differentiation. Considering that BDKRB1 is up‐regulated by inflammation and/or by cytokines that are abundant in the inflammatory milieu, more stable BDKRB1 agonists may be of therapeutic value to modulate wound healing.
ISSN:0906-6705
1600-0625
DOI:10.1111/exd.13038