Iron is both necessary for normal metabolism and a danger to homeostasis(1). Our preliminary studies suggest that iron is essential for normal responses to cytokine stimulation characteristic of cutaneous inflammatory responses. Previous studies examining cutaneous responses to LTV light also suggests a role for iron in induction of clinical erythema (2) as well as induction of proteinases linked to photoaging (3). Our hypothesis is that free intracellular iron in the ferrous state (Fe+2) is an important constituent of the cytokine mediating signaling cascade by participating in the generation of oxidative signaling intermediate that plays an important role in the activation of specific pro-inflammatory genes. The evidence for iron in the induction of inducible adhesion molecules in endothelial cells is indirect, relying on the use of iron chelating agents such as dipyridyl (DP). In order to define the pathways involved in the iron-dependent signaling pathways in endothelial cells, we will:
Specific aim 1 : Examine whether DP treatment alters the expression of intracellular free iron levels, intracellular reactive oxygen species in tumor necrosis factor alpha (TNFalpha)-treated human dermal microvascular endothelial cells (HDMEC) and whether these species are important in VCAM-1 gene expression.
Specific aim 2 : Examine whether DP pretreatment prior to TNF stimulation inhibits increases in steady-state VCAM-1 mRNA by altering mRNA stability and/or gene transcription.
Specific aim 3 : Examine whether DP treatment affects the expression of or phosphorylation of the transcription factors p65 or interferon regulatory factor 1 (IRF-1).
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