Original Article
Subject Category: Keratinocytes/Epidermis
Journal of Investigative Dermatology (2005) 124, 178–186; doi:10.1111/j.0022-202X.2004.23518.x
Kinin B2 Receptor-Coupled Signal Transduction in Human Cultured Keratinocytes
Maria A Vidal*, Angel Astroza*, Carola E Matus*, Pamela Ehrenfeld*, Francisca Pavicic*, Tamara Sanchez*, Christian Salem†, Jaime Figueroa‡, Miguel Concha*, Carlos B Gonzalez§ and Carlos D Figueroa*
- *Institutos de Histología y Patología Universidad Austral de Chile, Valdivia, Chile
- †Institutos de Cirugía, Universidad Austral de Chile, Valdivia, Chile
- ‡Institutos de Bioquímica; Universidad Austral de Chile, Valdivia, Chile
- §Institutos de Fisiología, Universidad Austral de Chile, Valdivia, Chile
Correspondence: Carlos D. Figueroa PhD, Instituto de Histología y Patología, Universidad Austral de Chile, Casilla 567, Isla Teja, Valdivia, Chile. Email: cfiguero@uach.cl
Received 12 March 2004; Revised 10 July 2004; Accepted 5 August 2004; Published online 21 December 2004.
Abstract
Kinins are key pro-inflammatory peptides that exhibit mitogenic effects in tissue-specific cellular systems. Since the life span of the keratinocyte is regulated by receptors that control proliferation and differentiation, and since both processes are affected during wound healing, we have examined the consequence of kinin B2 receptors (B2R) activation in cultured human keratinocytes. Stimulation of keratinocytes by Lys-bradykinin (LBK) induced a rapid and sustained phosphorylation of 42/44 mitogen-activated protein kinase (MAPK) that translocated to the nucleus, and decreased only after 120 min of stimulation. Kinin B1 and B2 receptor (B1R and B2R) antagonists showed that phosphorylation was mainly because of B2R activation. The GF109203X inhibitor almost completely abolished the effect of LBK, suggesting the involvement of protein kinase C in the signal cascade. MAPK phosphorylation was partially dependent on epidermal growth factor receptor transactivation as assessed by the selective inhibitor, AG1478. LBK stimulation did not result in cell proliferation, but produced a rapid c-Fos expression, nuclear translocation of nuclear factor-
B, and a moderated (pro)filaggrin synthesis, indicating that it may modulate cell differentiation. Our results support the view that kinins may affect the life span of human keratinocytes and highlight the importance that kinin peptides may have in the pathogenesis and/or progression of skin diseases.
Keywords:
kallikrein, keratinocyte differentiation, keratinocyte proliferation, kinins, kinin B2 receptor, MAPK, signal transduction
Abbreviations:
AU, arbitrary units; B2R, kinin B2 receptor; BK, bradykinin; BrdU, 5-bromo-2'-deoxyuridine; BSA, bovine serum albumin; EGFR, epidermal growth factor receptor; HOE140, kinin B2R antagonist; IgG, immunoglobulin; LBK, Lys-bradykinin; MAPK, 42/44 mitogen-activated protein kinase; NF-B, nuclear factor-B; PKC, protein kinase C; PMA, phorbol 12-myristate 13-acetate; P-MAPK, phosphorylated MAPK; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; T-MAPK, total MAPK
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