Glycobiology and Extracellular Matrices
Low Dose Ultraviolet B Irradiation Increases Hyaluronan Synthesis in Epidermal Keratinocytes via Sequential Induction of Hyaluronan Synthases Has1–3 Mediated by p38 and Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) Signaling*,

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Hyaluronan, a major epidermal extracellular matrix component, responds strongly to different kinds of injuries. This also occurs by UV radiation, but the mechanisms involved are poorly understood. The effects of a single ultraviolet B (UVB) exposure on hyaluronan content and molecular mass, and expression of genes involved in hyaluronan metabolism were defined in monolayer and differentiated, organotypic three-dimensional cultures of rat epidermal keratinocytes. The signals regulating the response were characterized using specific inhibitors and Western blotting. In monolayer cultures, UVB increased hyaluronan synthase Has1 mRNA already 4 h postexposure, with a return to control level by 24 h. In contrast, Has2 and Has3 were persistently elevated from 8 h onward. Silencing of Has2 and especially Has3 decreased the UVB-induced accumulation of hyaluronan. p38 and Ca2+/calmodulin-dependent protein kinase II pathways were found to be involved in the UVB-induced up-regulation of Has2 and Has3 expression, respectively, and their inhibition reduced hyaluronan deposition. However, the expressions of the hyaluronan-degrading enzymes Hyal1 and Hyal2 and the hyaluronan receptor Cd44 were also up-regulated by UVB. In organotypic cultures, UVB treatment also resulted in increased expression of both Has and Hyal genes and shifted hyaluronan toward a smaller size range. Histochemical stainings indicated localized losses of hyaluronan in the epidermis. The data show that exposure of keratinocytes to acute, low dose UVB increases hyaluronan synthesis via up-regulation of Has2 and Has3. The simultaneously enhanced catabolism of hyaluronan demonstrates the complexity of the UVB-induced changes. Nevertheless, enhanced hyaluronan metabolism is an important part of the adaptation of keratinocytes to radiation injury.

Background:

Accumulation of epidermal hyaluronan is an early event in UVB-induced squamous cell carcinomas.

Results:

UVB increases keratinocyte hyaluronan synthesis by up-regulating hyaluronan synthases Has1 and -2 via p38 and Has3 via Ca2+/calmodulin-dependent protein kinase II (CaMKII) signaling.

Conclusion:

UVB triggers deposition of epidermal hyaluronan through at least two signaling pathways.

Significance:

Increased hyaluronan synthesis is an inherent feature of keratinocyte adaptation to radiation injury.

CaMKII
Epidermis
Hyaluronate
Keratinocytes
p38
UVB
Hyaluronan Synthase (HAS)

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*

This work was supported by grants from Tekes (to R. T.), the Cancer Center of the University of Eastern Finland (to R. T. and M. T.), and the Juselius Foundation (to R. T. and M. T.).

This article contains supplemental Tables 1–3 and Figs. 1–6.