Abstract
Simple SummaryKonjac ceramide (kCer) is a unique molecular species of plant-type ceramide, and is a potential Sema3A-like ligand of Nrp1. kCer suppresses histamine-stimulated cell migration of HaCaT keratinocytes. This effect of kCer is not due to histamine-activated GPCRs, but rather to Sema3A-Nrp1 receptor binding. The present study focused on the ability of kCer to induce cell differentiation, in addition to its anti-migratory effects. We demonstrated that the effects of kCer on cell migration and cell differentiation are perpetuated by a cascade of crosstalk between pathways downstream of Nrp1 and GPCR in HaCaT cells.Histamines suppress epidermal keratinocyte differentiation. Previously, we reported that konjac ceramide (kCer) suppresses histamine-stimulated cell migration of HaCaT keratinocytes. kCer specifically binds to Nrp1 and does not interact with histamine receptors. The signaling mechanism of kCer in HaCaT cells is also controlled by an intracellular signaling cascade activated by the Sema3A-Nrp1 pathway. In the present study, we demonstrated that kCer treatment induced HaCaT keratinocyte differentiation after migration of immature cells. kCer-induced HaCaT cell differentiation was accompanied by some features of keratinocyte differentiation markers. kCer induced activating phosphorylation of p38MAPK and c-Fos, which increased the protein levels of involucrin that was the latter differentiation marker. In addition, we demonstrated that the effects of both kCer and histamines are regulated by an intracellular mechanism of Rac1 activation/RhoA inhibition downstream of the Sema3A/Nrp1 receptor and histamine/GPCR pathways. In summary, the effects of kCer on cell migration and cell differentiation are regulated by cascade crosstalk between downstream Nrp1 and histamine-GPCR pathways in HaCaT cells.
Highlights
Ceramides have been extensively used as supplements to prevent lifestyle-related diseases such as dry skin [1]
The long-chain bases included in konjac produced by EGCase treatment are indicated by a dotted rectangle. (C) konjac ceramide (kCer) ceramide molecular(kCer) species produced by EGCase treatment are indicated by a dotted rectangle. (C) kCer molecular species generated by EGCase treatment of Konjac GlcCer (kGlcCer)
We demonstrated that HaCaT cell differentiation occurs after cell migration in cells treated with kCer
Summary
Ceramides have been extensively used as supplements to prevent lifestyle-related diseases such as dry skin [1]. In plant tissue, free ceramide is composed of glycosylinositol phosphoceramide (GIPC) and GlcCer [3]. The remarkable differences in the molecular structures of animal and plant ceramides is attributed to a diversity of long-chain bases (Figure 1B). Molecular species of kCer are characterized by the combination of long-chain bases (d18:2, t18:1) and 2hydroxyl fatty acids of C16:0, C18:0, C20:0, C22:0, C23:0, and C24:0 (Figure 1C) [4]
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