Kinin B2 Receptor-Coupled Signal Transduction in Human Cultured Keratinocytes

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-kappaB, 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.

Bradykinin stimulates glutamate uptake via both B1R and B2R activation in a human retinal pigment epithelial cells

“…This result is in agreement with the finding that a tyrosine kinase inhibitor blocked the effect of BK in MDCK cells (Xing et al, 1997). However, we cannot rule out the possibility that BK induces the phosphorylation of other proteins, since BK induces the phosphorylation of p44/42 MAPKs and src in keratinocytes (Vidal et al, 2005).…”

B1 and B2 kinin receptor participation in hyperproliferative and inflammatory skin processes in mice

“…Several studies have reported that kinins may increase DNA synthesis and cell division in several cellular systems [26]. Nevertheless, some data are contradictory and state that kinins do not stimulate keratinocyte proliferation [27][28][29] or induce a weak response when compared with that produced by epidermal growth factor (EGF) [30]. These previously mentioned works were performed in vitro and some used epidermal scales of psoriatic patients.…”

Stimulation of the bradykinin B1 receptor induces the proliferation of estrogen-sensitive breast cancer cells and activates the ERK1/2 signaling pathway

“…Bound antibodies were detected using a chemiluminescence kit (Pierce, USA). The antibodies used for the first immunodetection were stripped as previously described [15] and total amount of ERK1/2 present in each sample was assessed using a polyclonal antibody (Cell Signaling). Specificity was evaluated by pre-incubating cells for 30 min with an excess of a B 1 R (des-[Arg 9 ]-Leu 8 -BK or Lys-des-[Arg 9 ]-Leu 8 -BK, Bachem), or a B 2 R antagonists before stimulation.…”