Mechanisms of augmented UVB immunosuppressive responses by polyaromatic hydrocarbons - Abstract
Humans are subjected daily to multiple and often simultaneous environmental stressors, yet the complex
interaction of these agents remains an understudied area. Of significance, the exposure to environmental
ultraviolet radiation (UVR) has profound effects on the skin and induces systemic consequences from vitamin D
production to immunosuppression to melanoma and non-melanoma skin cancers. Besides, ubiquitous
environmental pollutants, polycyclic aromatic hydrocarbons (PAH) exert immunomodulatory as well as pro-
carcinogenic effects. However, there is a significant knowledge gap of interactions between UVR and pollutants,
including the mechanisms of their combined effects leading to disease pathophysiology such as skin cancer.
Recent studies, including ours, have indicated that small membrane-bound vesicles known as microvesicle
particles (MVP) released from cells in response to various stressors can act as potent signaling agents due to
their ability to carry nuclear and cytoplasmic components. We have demonstrated that UVB, due to its ability to
generate reactive oxygen species (ROS), produces high levels of the lipid mediator Platelet-activating factor
(PAF) agonists and MVP from epithelial cells and skin. Notably, recent studies using PAFR-expressing/null cell
lines and pharmacologic/genetic inhibition of ROS, and the enzyme acid sphingomyelinase (aSMase) have
implicated the involvement of the PAF-receptor (PAFR) signaling in aSMase activation resulting in UVB-
generated MVP (UVB-MVP) release. These UVB-MVP carry bioactive PAF agonists, and mediate UVB-induced
delayed immunosuppressive effects. Importantly, we discovered that the PAH Benzo[a]pyrene (BaP) interaction
with UVB releases high levels of UVB-MVP and generates increased levels of PAF agonists. As other ROS-
generating PAH compounds such as anthracene, chrysene, and pyrene are natural components of
environmental pollutants and associated with disease pathophysiologies, including lung/skin cancer mortality,
we propose one specific aim to test the hypothesis that these PAHs will exert synergistic effects with UVB in the
generation of ROS, PAF-agonists, and MVPs involving the PAFR and acid sphingomyelinase (aSMase)
pathways. Aim 1 will use in vitro cell lines and pharmacologic inhibitors to determine the role and mechanisms
of these PAHs and UVB in the generation of ROS, PAF, and MVP. Successful completion of this project will (i)
define a novel mechanism by which a PAH pollutant can augment UVR-induced effects; and ii) address an
important question in photobiology as to how a keratinocyte-specific stimulus can generate systemic signaling
effects. Importantly, this supplement project will provide mentorship, required skills and knowledge to a talented
applicant and assist her transition to an independent health care research career path in the future.
