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. 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.
Instituto de Morfofisiología y Farmacología, Universidad Austral de Chile, Valdivia, Chile.
Carola E
CE
Matus
Laboratorio de Patología Celular, Instituto de Anatomía, Histología & Patología, Universidad Austral de Chile, Valdivia, Chile.
Pamela
P
Ehrenfeld
Laboratorio de Patología Celular, Instituto de Anatomía, Histología & Patología, Universidad Austral de Chile, Valdivia, Chile.
Francisca
F
Pavicic
Instituto de Fisiología, Universidad Austral de Chile, Valdivia, Chile.
Carlos B
CB
González
Laboratorio de Patología Celular, Instituto de Anatomía, Histología & Patología, Universidad Austral de Chile, Valdivia, Chile.
Miguel
M
Concha
Laboratorio de Patología Celular, Instituto de Anatomía, Histología & Patología, Universidad Austral de Chile, Valdivia, Chile.
Kanti D
KD
Bhoola
Instituto de Morfofisiología y Farmacología, Universidad Austral de Chile, Valdivia, Chile.
Rafael A
RA
Burgos
Laboratorio de Patología Celular, Instituto de Anatomía, Histología & Patología, Universidad Austral de Chile, Valdivia, Chile.
Carlos D
CD
Figueroa
D000072198:ADAM17 Protein / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D066246:ErbB Receptors / Q000378:metabolism*; D007609:Kallidin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015603:Keratinocytes / Q000201:enzymology / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D043783:Receptor, Bradykinin B1 / Q000819:agonists* / Q000378:metabolism; D015533:Transcriptional Activation; D014945:Wound Healing / Q000187:drug effects*; D019061:src-Family Kinases / Q000378:metabolism
D043783:Receptor, Bradykinin B1; D007609:Kallidin; C052787:kallidin, des-Arg(10)-; C512478:EGFR protein, human; D066246:ErbB Receptors; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D000072198:ADAM17 Protein
B1 bradykinin receptor; epidermal growth factor receptor; metalloproteases; transactivation; wound healing