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Evidence for a proinflammatory role of proteinase‐activated receptor‐2 during cutaneous inflammation in vivo
Author(s) -
Steinhoff M.,
Seeliger S.,
Derian C.,
Nawroth R.,
Sunderkötter C.,
Metze D.,
Vestweber D.,
AndradeGordon P.,
Luger T. A.
Publication year - 2004
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/j.0906-6705.2004.0212cm.x
Subject(s) - inflammation , proinflammatory cytokine , immunology , extravasation , cell adhesion molecule , leukocyte extravasation , receptor , chemistry , medicine , biochemistry
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.