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- W2794838961 abstract "4672 Tpl2 is a serine/threonine protein kinase implicated in the regulation of cellular proliferation, differentiation, and immune response involving chemokine-cytokine production. Tpl2 knockout mice do not display an overt phenotype and have histologically normal bone marrow, thymus, spleen, and lymph nodes. In the mouse skin carcinogenesis model, short-term (one time) application of phorbol esters (TPA) to mouse skin results in an acute inflammatory response and epidermal hyperplasia. Repeated long-term application of TPA (after initiation with DMBA) leads to tumor formation in susceptible mice. We hypothesized that loss of Tpl2 will lead to a dampened inflammatory response and loss of tumorigenic response to TPA. Tpl2 knockout mouse skins were treated with TPA over 4 to 48 hours to assess the short-term role of Tpl2 in skin inflammatory response and hyperplasia. Long-term treatment with TPA for 30 weeks, after initiation with DMBA, was performed to assess the tumorigenic potential versus wildtype controls. Unexpectedly, the inflammatory response of the knockout mice to TPA application was stronger, appeared earlier, and lasted longer than the wild type mice. This was characterized by infiltrating neutrophils, macrophages, mast cells, and occasional lymphocytes. The enhanced inflammatory response was due to differential expression of cytokines including IL-2, IL-1beta, KC, MIP-1alpha, IL-5 and G-CSF. Long-term carcinogenesis experiments reveled unexpected skin tumor development in the knockout mice after only 9 weeks of TPA application. By 30 weeks, 87% of the knockout animals had a mean of 4 tumors/animal as compared to only 17% of wild type mice with a mean of 1.25 tumors/animal. These results indicate that loss of Tpl2 has led to potentiation of a compensatory pathway. This study validates in-vitro data and indicates that potentiation of the Ras/Erk pathway may be responsible for this unchecked early inflammatory response and enhanced skin carcinogenesis in response to TPA treatment." @default.
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- W2794838961 date "2007-05-01" @default.
- W2794838961 modified "2023-09-28" @default.
- W2794838961 title "Skin inflammation and carcinogenesis enhanced in Tpl2 knockout mouse model" @default.
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