The Attenuated Secretion of Hyaluronan by UVA-Exposed Human Fibroblasts Is Associated with Up- and Downregulation of HYBID and HAS2 Expression via Activated and Inactivated Signaling of the p38/ATF2 and JAK2/STAT3 Cascades.

Shuko Terazawa,Mariko Takada,Genji Imokawa,Yoriko Sato,Hiroaki Nakajima

doi:10.3390/ijms22042057

Shuko Terazawa, Mariko Takada + Show 3 more

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https://doi.org/10.3390/ijms22042057

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Abstract

Little is known about the effects on hyaluronan (HA) metabolism of UVA radiation. This study demonstrates that the secretion of HA by human dermal fibroblasts (HDFs) is downregulated by UVA, accompanied by the down- and upregulation of mRNA and protein levels of the HA-synthesizing enzyme (HAS2) and the HA-degrading protein, HYaluronan Binding protein Involved in HA Depolymerization(HYBID), respectively. Signaling analysis revealed that the exposure distinctly elicits activation of the p38/MSK1/CREB/c-Fos/AP-1 axis, the JNK/c-Jun axis, and the p38/ATF-2 axis, but downregulates the phosphorylation of NF-kB and JAK/STAT3. A signal inhibition study demonstrated that the inhibition of p38 significantly abrogates the UVA-accentuated mRNA level of HYBID. Furthermore, the inhibition of STAT3 significantly downregulates the level of HAS2 mRNA in non-UVA exposed HDFs. Analysis using siRNAs demonstrated that transfection of ATF-2 siRNA but not c-Fos siRNA abrogates the increased protein level of HYBID in UVA-exposed HDFs. An inhibitor of protein tyrosine phosphatase but not of protein serine/threonine phosphatase restored the diminished phosphorylation level of STAT3 at Tyr 705, accompanied by a significant abolishing effect on the decreased mRNA expression level of HAS2. Silencing with a protein tyrosine phosphatase PTP-Meg2 siRNA revealed that it abrogates the decreased phosphorylation of STAT3 at Tyr 705 in UVA-exposed HDFs. These findings suggest that the UVA-induced decrease in HA secretion by HDFs is attributable to the down- and upregulation of HAS2 and HYBID expression, respectively, changes that are mainly ascribed to the inactivated signaling of the STAT3 axis due to the activated tyrosine protein phosphatase PTP-Meg2 and the activated signaling of the p38/ATF2 axis, respectively.

Highlights

Hyaluronan (HA) is an essential constitutional biopolymer localized in the extracellular microenvironment of the dermis where it sustains the typical physicochemical and viscoelastic properties of the skin
As levels of HA in extracellular circumstances are regulated by the HA synthetic enzymes HAS1/2/3 and by the HA degradative protein HYBID [22], analysis of mRNA levels of those factors using real time qPCR revealed that the inhibitory effect of UVA on HA secretion is distinctly accompanied by the up- and downregulation of mRNA levels of HYBID and HAS2, respectively
The sum of these findings indicates that under the in vivo skin conditions, the UVA irradiation penetrates to the dermis and causes human dermal fibroblasts (HDFs) to downregulate HAS2 expression and to simultaneously upregulate HYBID expression, which results in the distinct deficiency and fragmentation of HA in the dermis

Summary

Introduction

Hyaluronan (HA) is an essential constitutional biopolymer localized in the extracellular microenvironment of the dermis where it sustains the typical physicochemical and viscoelastic properties of the skin. The three-dimensional linear microstructures of elastic fibers that are essential to support their elastic properties are abnormally curled and/or highly tortuous as a result of the accentuated expression of fibroblast-derived elastase neprilysin [1,6,7,8,9,10,11,12] Such deleterious tissue damage in the dermis results in the decreased elasticity of the skin, which leads to the subsequently increased incidence of skin wrinkles and sagging [1]. This close relationship is corroborated by our clinical observations that the formation or amelioration of facial wrinkles distinctly occurs accompanied by a marked loss or recovery of skin elastic properties, respectively [13,14,15]

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