Reduced skin inflammatory response in mice lacking inducible nitric oxide synthase.
The skin is the largest organ in the body and one of its main functions is to protect the body from environmental and endogenous noxious conditions, such as injury, infection and inflammation. The inducible nitric oxide synthase (iNOS) has been implicated as a key component in the inflammatory response. In the present study, we assessed the role of iNOS in the skin inflammation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). Mice deficient in iNOS had reduced edema and cellular infiltration in the skin following topical TPA application. Moreover, the genetic blockage of iNOS signaling inhibited the TPA-induced ERK and p38 activation resulting in reduced COX-2 upregulation. Finally, immunohistochemical studies revealed that iNOS knockout mice exhibited marked inhibition of AP-1, CREB and NF-kappaB transcriptional factors activation. Together, these results indicate that TPA induces the activation of several iNOS-dependent intracellular signaling pathways that have a key role in the control of inflammatory response in the skin. Therefore, selective iNOS inhibitors may be potentially relevant tools for cutaneous skin disease drug development.
Medeiros
Rodrigo
R
Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Santa Catarina, Brazil.
Figueiredo
Cláudia P
CP
Passos
Giselle F
GF
Calixto
João B
JB
D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D003872:Dermatitis / Q000209:etiology* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D010031:Otitis / Q000139:chemically induced*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D013755:Tetradecanoylphorbol Acetate