Abstract
Ultraviolet-B (UVB) irradiation of the skin can result in both acute inflammation and systemic immunosuppression. These effects are mediated by the release of bioactive molecules (e.g. cytokines and lipids) from resident skin epithelial and immune cells. Our lab has previously determined that UVB exposure stimulates the production of an inflammatory phospholipid activator, platelet-activating factor (PAF) and its oxidized analogs, which are involved in mediating the UVB responses. Due to the fact that UVB radiation is absorbed by the epidermis but causes systemic effects, we are interested in examining the PAF-mediated mechanisms of systemic intercellular communication. Microvesicle particles (MVP) are small membrane-derived vesicles released from the plasma membrane that can facilitate intercellular transport of bioactive molecules. We have previously reported that UVB induces MVPs in a PAF-dependent manner, but the mechanism is not fully characterized. It has been reported that in other cell types non-UVB cell stressors require sphingomyelin catabolic activity of acid sphingomyelinase (aSMase) and kinase-mediated signaling cascades for MVP release. In this study, both UVB and CPAF (PAFR agonist), stimulated MVP release in various skin-derived epithelial cell lines. The PAF dependence of UVB-mediated MVP release was confirmed utilizing a PAF antagonist and PAFR +/- cell lines. Imipramine, a small-molecule inhibitor of aSMase effectively blocked CPAF- and UVB-mediated MVP release suggesting that aSMase activity is required for these responses. Interestingly, CPAF mediated MVP release was suppressed by NF-ƙB, ERK ½, JNK, p38 MAPK and ROCK1 small molecule inhibitors, while UVB-mediated MVP release was only suppressed by the JNK, p38 MAPK, and ROCK1 inhibitors. These findings suggest common and distinct pathways between the two stimuli. Subsequently, this study has confirmed the role of PAF, lipid remodeling, and robust kinase signaling in UVB and PAF-mediated MVP release. The targeting of such mechanisms of UVB-mediated MVP release could have potential therapeutic benefits in mitigating UVB-induced acute inflammation and systemic immunosuppression.
Original language | American English |
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Journal | Default journal |
State | Published - May 10 2017 |
Keywords
- UVB
- aSMase inhibitors
- immunosuppression
- local inflammation
- microvesicle particles
- platelet-activating factor
- platelet-activating factor receptor
- ultraviolet light
Disciplines
- Chemicals and Drugs
- Medical Toxicology
- Medicine and Health Sciences