Prostaglandin E₂Enhances Neurotrophin-4 Production via EP3 Receptor in Human Keratinocytes

Abstract

Atopic dermatitis is characterized by increased skin innervation. The expression of neurotrophin-4 is enhanced in the epidermal keratinocytes of lesions with atopic dermatitis and may be related to hyperinnervation in these lesions. Prostaglandin E 2 (PGE 2 ) levels are increased in lesions with atopic dermatitis; thus, PGE 2 may be involved in the development of this disease. We examined the in vitro effects of PGE 2 on neurotrophin-4 production in human keratinocytes. PGE 2 and EP1/EP3 agonist sulprostone increased neurotrophin-4 secretion and mRNA levels without altering its mRNA stability. Antisense Sp1 oligodeoxynucleotide and Sp1 inhibitor mithramycin A suppressed PGE 2 and sulprostone-induced neurotrophin-4 expression, indicating the requirement for Sp1 for expression. PGE 2 or sulprostone markedly enhanced the phosphorylation, DNA binding, and transcriptional activity of Sp1 and modestly increased Sp1 mRNA and protein levels. PGE 2 or sulprostone induced the membrane translocation of protein kinase C␣ and the phosphorylation of extracellular signal-regulated kinase (ERK). PGE 2 -induced increases in neurotrophin-4 expression, Sp1 transcriptional and DNA-binding activity, Sp1 mRNA and protein levels, and ERK phosphorylation were suppressed by antisense EP3 oligodeoxynucleotide, inhibitors of phosphatidylinositol-specific phospholipase C, conventional protein kinase C, and mitogen-activated protein kinase/ERK kinase 1 (MEK1). These results suggest that PGE 2 enhances neurotrophin-4 production by activating Sp1 via the EP3/phosphatidylinositolspecific phospholipase C/protein kinase C␣/MEK1/ERK pathway. PGE 2 may promote innervation in skin lesions with atopic dermatitis via the induction of neurotrophin-4.

The role of the EP receptors for prostaglandin E2 in skin and skin cancer

“…Additionally, in atopic dermatitis, PGE 2 promotes the innervation of skin lesions through the activation of the EP3 receptor in keratinocytes, which subsequently induces neurotrophin-4. The signaling pathway utilized in this case is the phosphoinositol-specific PLC/PKCα/ERK pathway [76]. Thus, there are several examples of a pro-inflammatory role for the EP3 receptor in skin, although the signaling pathways utilized may depend on the etiological agent and/or isoforms that are activated.…”

The Epithelial Cell-Derived Atopic Dermatitis Cytokine TSLP Activates Neurons to Induce Itch

“…Indeed, many of the factors that keratinocytes secrete act on both immune cells and primary afferent sensory neurons (Andoh et al, 2001; Fitzsimons et al, 2001; Kanda et al, 2005; Ziegler et al, 2013). Thus, TSLP may evoke itch behaviors directly, by activating sensory neurons, indirectly, by activating immune cells that secrete inflammatory mediators that target sensory neurons, or both.…”

Participation of phosphatidyl inositol 3-kinase/protein kinase B and ERK1/2 pathways in interleukin-1β stimulation of lactate production in Sertoli cells

“…In addition, Ishikawa & Morris (2006) have proposed that an autocrine-amplifying loop that involves COX-2-induced PGE2 and PGF2a production participates in the IL1b-regulated Sertoli cell function. Considering that IL6, PGE2, and PGF2a stimulate ERK1/ 2 in other cell types (Lin et al 2001, Kanda et al 2005, Sales et al 2005, the participation of this pathway in relation to these other hormones, but not to IL1b, cannot be ruled out. However, taking into account that a preincubation with PD98059 or U0126 is necessary to observe the effect of the inhibitors on IL1b stimulation of LDH A mRNA levels, it is tempting to speculate that IL1b itself stimulates an ERK1/2 pathway that is related to the regulation of this biological response.…”