Abstract
Extracellular nucleotides, such as ATP, are released from cells in response to various stimuli and act as intercellular signaling molecules through activation of P2 receptors. Exposure to the ultraviolet radiation A (UVA) component of sunlight causes molecular and cellular damage, and in this study, we investigated the involvement of extracellular nucleotides and P2 receptors in the UVA-induced cellular response. Human keratinocyte-derived HaCaT cells were irradiated with a single dose of UVA (2.5 J/cm2), and ATP release and interleukin (IL)-6 production were measured. ATP was released from cells in response to UVA irradiation, and the release was blocked by pretreatment with inhibitors of gap junction hemichannels or P2X7 receptor antagonist. IL-6 production was increased after UVA irradiation, and this increase was inhibited by ecto-nucleotidase or by antagonists of P2Y11 or P2Y13 receptor. These results suggest that UVA-induced IL-6 production is mediated by release of ATP through hemichannels and P2X7 receptor, followed by activation of P2Y11 and P2Y13 receptors. Interestingly, P2Y11 and P2Y13 were associated with the same pattern of IL-6 production, though they trigger different intracellular signaling cascades: Ca2+-dependent and PI3K-dependent, respectively. Thus, IL-6 production in response to UVA-induced ATP release involves at least two distinct pathways, mediated by activation of P2Y11 and P2Y13 receptors.
Highlights
Long-term exposure to sunlight causes various detrimental effects to the skin, including skin cancer and premature aging, characterized by epidermal hyperplasia, wrinkles and mottled pigmentation [1, 2]
Our present results show that ultraviolet radiation A (UVA) irradiation of HaCaT cells induced Adenosine 5’-triphosphate (ATP) release
Since cell viability was unaffected by the same dose of UVA, cytosolic ATP must be released through a non-lytic mechanism(s)
Summary
Long-term exposure to sunlight causes various detrimental effects to the skin, including skin cancer and premature aging (photoaging), characterized by epidermal hyperplasia, wrinkles and mottled pigmentation [1, 2]. Solar radiation at the earth’s surface includes short-wavelength ultraviolet (UVB, 280–320 nm) and long-wavelength ultraviolet (UVA, 320–400 nm) components. Both are injurious, UVA radiation has been considered less carcinogenic and mutagenic because of its limited ability to cause direct DNA damage [3]. UVA radiation has been considered less carcinogenic and mutagenic because of its limited ability to cause direct DNA damage [3] For this reason, PLOS ONE | DOI:10.1371/journal.pone.0127919. UVA irradiation causes major changes in skin connective tissues as a result of the degradation of structural components of the extracellular matrix, in both epidermis and dermis [7, 8]. Since it has been suggested that alteration of skin tissues induces cutaneous aging, it is possible that UVA exposure plays an important role in the development of photoaging
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