UVA‐INDUCED AUTOCRINE STIMULATION OF FIBROBLAST‐DERIVED COLLAGENASE/MMP‐1 BY INTERRELATED LOOPS OFINTERLEUKIN–1 andINTERLEUKIN–6

Abstract

Previous work has shown that fibroblast-derived collagenase/matrix-metalloproteinase-1 (MMP-1), responsible for the breakdown of dermal interstitial collagen, was dose-dependently induced in vitro and in vivo by UVA irradiation and this induction was at least partly mediated by interleukin-6 (IL-6). We here provide evidence that UVA-induced IL-1 alpha and IL-1 beta play a central role in the induction of the synthesis both of IL-6 and collagenase/MMP-1. In contrast to the late increase of IL-1 alpha and IL-1 beta mRNA levels at 6 h postirradiation, bioactivity of IL-1 is already detectable at 1 h postirradiation. This early peak of IL-1 bioactivity appears to be responsible for the induction of IL-6 synthesis and together with IL-6 lead to an increase of the steady-state mRNA level of collagenase/MMP-1 as deduced from studies using IL-1 alpha and IL-1 beta antisense oligonucleotides or neutralizing antibodies against IL-1 alpha and IL-1 beta. Besides the early posttranslationally controlled release of intracellular IL-1, a latter pretranslationally controlled synthesis and release of IL-1 perpetuates the UV response. From these data we suggest a UV-induced cytokine network consisting of IL-1 alpha, IL-1 beta and IL-6, which via interrelated autocrine loops induce collagenase/MMP-1 and thus may contribute to the loss of interstitial collagen in cutaneous photoaging.

Overexpression of Phospholipid-hydroperoxide Glutathione Peroxidase in Human Dermal Fibroblasts Abrogates UVA Irradiation-induced Expression of Interstitial Collagenase/Matrix Metalloproteinase-1 by Suppression of Phosphatidylcholine Hydroperoxide-mediated NFκB Activation and Interleukin-6 Release

“…There are, however, several examples of the detrimental effects on life span and tissue integrity of a complete lack or imbalance in interdependent antioxidant enzymes occurring in genetic disorders, transgenic organisms, and cell biology (3,(57)(58)(59)(60)(61)(63)(64)(65)(66). 2 In fact, studies on transgenic Drosophila overexpressing interdependent antioxidant enzymes or mice deficient for the protooncogene pShc 66 reveal a better protection from oxidative injury and tissue degeneration resulting in a 30% increase in life span (65,66). Hence effective cellular protection requires a balance between interdependent antioxidant enzymes with an appropriate relationship to each other or the overexpression of a more central antioxidant enzyme, like the PHGPx, that protects from the effects of various reactive oxygen species by the detoxification of ROS-induced peroxides.…”

“…We focused on these regulatory key steps in the upstream signal transduction cascade finally leading to MMP-1 induction because we have shown previously that interleukin-6, via an autocrine loop, is mainly responsible for the UVA and UVB induction of MMP-1 (16,19,66). Unlike most transcription factors, the heterodimer complex of NFB, containing p50 and p65/RelA subunits (67)(68)(69)(70)(71), resides in the cytoplasm in a latent form and must therefore translocate into the nucleus to transactivate the IL-6 promoter (72).…”

Protecting Effect of Phytoncide Solution, on Normal Human Dermal Fibroblasts against Reactive Oxygen Species

“…Phytoncide solutions significantly suppressed the excess decrease in type I collagen and the production of MMP-1 following UVA irradiation in normal human dermal fibroblasts and human reconstructed skin model ( and ). It has been established that singlet oxygen produced in cells by UVA irradiation up-regulates MMP-1 gene transcription 26) . Also, phytoncide solutions reduced the damage to normal human dermal fibroblasts exposed to UVA.…”

UVA exposure of human skin reconstructed in vitro induces apoptosis of dermal fibroblasts: subsequent connective tissue repair and implications in photoaging

“…Studies on fibroblast or keratinocyte cultures revealed that through the generation of oxidative species (Tyrell and Keyse, 1990), UVA induces a decrease in Epidermal Growth Factor (EGF) binding (Djavaheri-Mergny et al, 1994), a modification of phospholipid metabolism (Hanson and deLeo, 1990) and lipid peroxidation (Morlie Á re et al, 1991;Moysan et al, 1995). In addition, UVA also leads to the production of extracellular degrading enzymes, stromelysin 1 and interstitial collagenase (Petersen et al, 1995;Sawamura et al, 1996;Scharffetter et al, 1991Scharffetter et al, , 1993Wlaschek et al, 1994Wlaschek et al, , 1995.…”