ISSN:
1600-0625
Source:
Blackwell Publishing Journal Backfiles 1879-2005
Topics:
Medicine
Notes:
Contact dermatitis (CD) is a frequent dermatological disease with a high socioeconomical impact characterized by acute to chronic inflammation of the skin, often leading to therapy-resistent eczema. Proteinase-activated receptor-2 (PAR-2), a G-protein-coupled receptor for certain serine proteases, is localized on keratinocytes, endothelial cells, and nerve fibers and has been demonstrated to play a role during inflammation of several tissues. However, the precise role of PAR-2 and the underlying mechanism of PAR-2-induced regulation of inflammation are still fragmentary. Therefore, we were interested in whether or not PAR-2 is involved in cutaneous inflammation using a model of experimentally induced allergic (ACD) and irritant (ICD) contact dermatitis. In wild-type (PAR-2+/+) mice, PAR-2 agonists induced an increased intradermal edema and enhanced plasma extravasation with a maximum between 3 and 24 h. These inflammatory responses were significantly diminished in PAR-2-deficient (PAR2–/–) mice and controls (vehicle). Morphological analysis revealed a dramatic increase of spongiosis and intradermal edema along with enhanced infiltration of neutrophils and monocytes in PAR-2+/+ mice as compared with PAR-2–/– mice. Interestingly, nitric oxide (NOS) inhibitors significantly diminished these effects, indicating a role of NO in PAR-2-induced inflammatory responses of the skin. Functional studies at the RNA and protein level further revealed PAR-2-induced upregulation of the cell adhesion molecules ICAM-1 and E-selectin by dermal microvascular endothelial cells during inflammation, suggesting that PAR-2 directly regulates cell adhesion molecule function during skin inflammation. PAR-2 agonists also stimulated upregulation of mediators involved in cutaneous inflammatory responses such as IL-6 and NO in murine and human (dermal) endothelial cells. Together, these results strongly suggest a proinflammatory role of PAR-2 during CD and probably other inflammatory dermatoses, especially during the early phase characterized by edema, plasma extravasation, and recruitment of inflammatory cells to the site of inflammation. Thus, PAR-2 antagonists may be therapeutic tools for the treatment of inflammatory skin disorders such as contact dermatitis and atopic eczema.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1111/j.0906-6705.2004.0212cm.x
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