afimoxifene and Psoriasis

Raf is one of the downstream effectors of Ras GTPases, and plays a key role in regulating cell proliferation and differentiation through the activation of MAPK. We have previously demonstrated that temporal induction of Raf in the epidermis of K14-Raf:ER transgenic mice results in epidermal hyperplasia resembling squamous cell carcinoma and psoriasis. It has been demonstrated that epidermal Stat3 activation is required for psoriasis development, since keratinocyte-specific Stat3 activation in a mouse model elicits a psoriasis-like phenotype, which is reversed by inhibition of Stat3 signaling.. The aim of this study was whether Stat3 signaling is involved in Raf-MAPK-dependent epidermal hyperplasia.. K14-Raf:ER transgenic mice, in which the 4-hydroxytamoxifen (4OHT)-responsive mutant estrogen receptor ligand binding domain-Raf fusion gene is expressed under control of the keratin 14 promoter, were mated with epidermis-specific Stat3 null mice (K5-Cre.Stat3(flox/flox)). K5-Cre.Stat3(flox/flox) mice were used to define the impact of Stat3 deficiency on Raf-induced epidermal hyperplasia.. Over-expression of Raf by 4OHT treatment in K14-Raf:ER;K5-Cre.Stat3(flox/flox) mice greatly attenuated the epidermal hyperplasia and dermal cell infiltrates compared with K14-Raf:ER;K5-Cre.Stat3(flox/WT) mice. Also, up-regulation of psoriasis-associated cytokine profiles, including VEGF, was inhibited in the skin from K14-Raf:ER;K5-Cre.Stat3(flox/flox) mice following 4OHT treatment.. These results clearly indicate that Raf-MAPK-dependent psoriatic-like epidermal hyperplasia requires Stat3 signaling in keratinocytes.

Topics: Animals; Carcinoma, Squamous Cell; Cell Differentiation; Epidermis; Gene Expression Regulation; Humans; Hyperplasia; Keratinocytes; Ligands; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mutation; Phenotype; Psoriasis; raf Kinases; Receptors, Estrogen; Signal Transduction; STAT3 Transcription Factor; Tamoxifen

Raf is one of the downstream effectors of Ras GTPases. The induction of Raf in the epidermis causes the proliferation of keratinocytes and epidermal hyperplasia. However, skin inflammation accompanying Ras-induced epidermal reactions has not been fully delineated.. The aim of this study was to characterize inflammatory reactions induced by epidermal-specific Raf expression and to elucidate its role in skin inflammation.. K14-Raf:ER transgenic mice, in which the 4-hydroxytamoxifen (4OHT)-responsive mutant estrogen receptor (ER) ligand binding domain-Raf fusion gene was expressed under control of the keratin 14 promoter, were used to characterize inflammatory reactions induced by Raf expression in the epidermis.. A single topical application of 4OHT induced the expression of phosphorylated extracellular signal-related kinase 1/2 and elicited neutrophil-dominant inflammatory infiltrates in the skin. The Raf expression also rapidly induced the production of several cytokines and chemokines, including VEGF and CXCL1, by keratinocytes and inmouse skin in vivo. Furthermore, CD4-positive cells from regional lymph nodes had the potential to differentiate into IFNg- and IL17-producing cells. Treatment with an anti-Gr-1 antibody diminished the Raf-induced cutaneous inflammation and partially reversed the epidermal hyperplasia and hyperkeratosis.. Activation of the Raf signaling pathway is involved in the epidermal hyperplasia and the neutrophil-dominant cutaneous inflammatory reactions which are characteristics of psoriasis.

Topics: Animals; CD4 Antigens; Chemokine CXCL1; Epidermis; Extracellular Signal-Regulated MAP Kinases; Humans; Hyperplasia; Interferon-gamma; Interleukin-17; Keratin-14; Lymph Nodes; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neutrophils; Promoter Regions, Genetic; Psoriasis; raf Kinases; Receptors, Estrogen; Tamoxifen; Vascular Endothelial Growth Factor A