Abstract
Exposure to ultraviolet-B (UVB) radiation induces inflammation and photocarcinogenesis in mammalian skin. Docosahexaenoic acid (DHA), a representative ω-3 polyunsaturated fatty acid, has been reported to possess anti-inflammatory and chemopreventive properties. In the present study, we investigated the molecular mechanisms underlying the inhibitory effects of DHA on UVB-induced inflammation in mouse skin. Our study revealed that topical application of DHA prior to UVB irradiation attenuated the expression of cyclooxygenase-2 (COX-2) and NAD(P)H:oxidase-4 (NOX-4) in hairless mouse skin. DHA pretreatment also attenuated UVB-induced DNA binding of nuclear factor-kappaB (NF-κB) through the inhibition of phosphorylation of IκB kinase-α/β, phosphorylation and degradation of IκBα and nuclear translocation of p50 and p65. In addition, UVB-induced phosphorylation of p65 at the serine 276 residue was significantly inhibited by topical application of DHA. Irradiation with UVB induced phosphorylation of mitogen and stress-activated kinase-1 (MSK1), extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein (MAP) kinase, and all these events were attenuated by pretreatment with DHA. Blocking ERK and p38 MAP kinase signaling by U0126 and SB203580, respectively, diminished MSK1 phosphorylation in UVB-irradiated mouse skin. Pretreatment with H-89, a pharmacological inhibitor of MSK1, abrogated UVB-induced activation of NF-κB and the expression of COX-2 and NOX-4 in mouse skin. In conclusion, topically applied DHA inhibits the UVB-induced activation of NF-κB and the expression of COX-2 and NOX-4 by blocking the phosphorylation of MSK1, a kinase downstream of ERK and p38 MAP kinase, in hairless mouse skin.
Highlights
Ultraviolet B (UVB) radiation is the most prevalent environmental carcinogen that increases the risk of skin cancer [1]
NOX is involved in UVB-induced generation of reactive oxygen species (ROS) in human keratinocytes [9], it is yet to be investigated if UVB irradiation can induce NOX-4 expression in mouse skin in vivo
We have previously reported that irradiation with UVB (180 mJ/cm2) induces COX-2 expression in HR-1 hairless mouse skin maximally at 6 h [26]
Summary
Ultraviolet B (UVB) radiation is the most prevalent environmental carcinogen that increases the risk of skin cancer [1]. Oxidative stress and persistent inflammation are the key pathologic events in UVB-induced skin photocarcinogenesis [2]. NAD(P)H:oxidases (NOX), a family of inducible membrane bound and cytosolic enzymes, is involved in the generation of reactive oxygen species (ROS) [3]. The expression and activity of different isoforms of NOX are elevated in various human cancers [4,5]. NOX-4, a member of the NOX family proteins, is an oncoprotein [6] that contributes to the transformation, proliferation and migration of cancer cells [7,8]. NOX is involved in UVB-induced generation of ROS in human keratinocytes [9], it is yet to be investigated if UVB irradiation can induce NOX-4 expression in mouse skin in vivo
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