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リエゾンラボ研究会
発表内容

Title:
Spred-2, a negative regulator of MAP kinase cascade, controls inflammatory responses

Akihiro Matsukawa MD, PhD.
Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University

Abstract:
Cytokines have been implicated in the progression of inflammatory responses , in which mitogen-activated protein (MAP) kinase cascades may play a role . Here, we demonstrate the role of Spred-2, a member of the Sprouty family proteins that negatively regulate the MAP kinase cascade, in murine models of inflammation. In acetaminophen (APAP) induced- hepatitis model, liver injury in Spred-2KO mice were much severer than that in the wild-type (WT) mice, as evidenced by increased serum levels of ALT, exacerbated hepatic injured area and reduced mice survival relative to the WT mice. TUNEL-positive hepatocytes were augmented in the liver from Spred-2KO mice. Activities of caspase-3, -8, and -9 were significantly elevated in Spred-2KO liver . FACS analyses demonstrated that the number of hepatic NK cells in Spred-2KO liver were significantly higher than those in the WT control. In addition, elevated levels of cytokines and chemokines were found in Spred-2KO mice relative to the WT mice. In ConA-hepatitis model, the liver injury in Spred-2KO mice was also exacerbated relative to the WT mice . Spred-2KO mice demonstrated higher levels of circulating cytokines such as IFNg and IL-17 compared to the WT mice. T he numbers of hepatic CD4+T cells in Spred-2KO liver were significantly higher than those in the WT control. In a sepsis model induced by cecal ligation and puncture (CLP), Spred-2 KO mice were resistant to the lethality relative to the WT mice. Bacterial burden in Spred-2 KO mice were significantly lower than WT mice, which was accompanied by increased phagocytic activities of macropohages. ROS production was also elevated in Spred-2KO macrophages. Thus, Spred-2 appears to play essential roles in inflammation, suggesting that Spred-2 may be a therapeutic target in the treatment of refractory inflammation. The role of Spred-2 in carcinogenesis related to inflammation will be also discussed.

References:
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