Biological Mechanisms Underlying the Ultraviolet Radiation-Induced Formation of Skin Wrinkling and Sagging II: Over-Expression of Neprilysin Plays an Essential Role

Abstract

Our previous studies strongly indicated that the up-regulated activity of skin fibroblast-derived elastase plays a pivotal role in wrinkling and/or sagging of the skin via the impairment of elastic fiber configuration and the subsequent loss of skin elasticity. Fortunately, we succeeded in identifying human skin fibroblast-derived elastase as a previously known enzyme, neprilysin or neutral endopeptidase (NEP). We have also characterized epithelial-mesenchymal paracrine cytokine interactions between UVB-exposed-keratinocytes and dermal fibroblasts and found that interleukin-1α and granulocyte macrophage colony stimulatory factor (GM-CSF) are intrinsic cytokines secreted by UVB-exposed keratinocytes that stimulate the expression of neprilysin by fibroblasts. On the other hand, direct UVA exposure of human fibroblasts significantly stimulates the secretion of IL-6 and also elicits a significant increase in the gene expression of matrix metallo-protease(MMP)-1 as well as neprilysin (to a lesser extent), which is followed by distinct increases in their protein and enzymatic activity levels. Direct UVA exposure of human keratinocytes also stimulates the secretion of IL-6, IL-8 and GM-CSF but not of IL-1 and endothelin-1. These findings suggest that GM-CSF secreted by UVA-exposed keratinocytes as well as IL-6 secreted by UVA-exposed dermal fibroblasts play important and additional roles in UVA-induced sagging and wrinkling by up-regulation of neprilysin and MMP-1, respectively, in dermal fibroblasts.

Particulate matter induces pro‐inflammatory cytokines via phosphorylation of p38 MAPK possibly leading to dermal inflammaging

“…Recent studies have indicated that communication between the dermal and epidermal layers is essential for the correct function and regulation of skin homeostasis. Complex signalling networks established between the two major cellular components of the skin (keratinocytes and fibroblasts) have proven to be critical in numerous processes such as those involving skin cell growth and differentiation, tissue repair, and wound healing and in processes modulating aesthetic features such as the presence of wrinkles and firmness . Keratinocytes have been reported to synthesize and secrete cytokines such as interleukin (IL)1, IL6, IL8, tumor necrosis factor (TNF)‐alpha, and transforming growth factor‐alpha and −beta .…”

“…Complex signalling networks established between the two major cellular components of the skin (keratinocytes and fibroblasts) have proven to be critical in numerous processes such as those involving skin cell growth and differentiation, tissue repair, and wound healing and in processes modulating aesthetic features such as the presence of wrinkles and firmness. [7] Keratinocytes have been reported to synthesize and secrete cytokines such as interleukin (IL)1, IL6, IL8, tumor necrosis factor (TNF)-alpha, and transforming growth factor-alpha and − beta. [8] There is evidence that keratinocytes stimulate fibroblasts to synthesize growth factors, which in turn will stimulate keratinocyte proliferation in a double paracrine manner.…”

Facial Skin Lifting and Brightening Following Sleep on Copper Oxide Containing Pillowcases

“…This results in changes of the skin's structure and appearance, including a marked loss of skin elasticity and recoil, increased appearance of wrinkles and facial sagging skin, especially under the eyes [7][8][9][10][11]. External influences, such as UV radiation, which may cause appearance of sunspots and uneven skin color, can also cause reduced skin elasticity, wrinkling and sagging [12,13].…”

Pterocarpus santalinus L. Regulated Ultraviolet B Irradiation‐induced Procollagen Reduction and Matrix Metalloproteinases Expression Through Activation of TGF‐β/Smad and Inhibition of the MAPK/AP‐1 Pathway in Normal Human Dermal Fibroblasts

“…Imokawa et al . found inflammatory cytokine IL‐6, which elicited upregulation of neprilysin and MMP‐1, was a powerful stimulator for skin photoaging. In addition, UVB‐induced reactive oxygen species (ROS) accelerated MMPs expression via the activation of mitogen‐activated protein kinase (MAPK)/activator protein 1 (AP‐1) pathway .…”