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The transcription factor kruppel-like factor 2 (KLF2) is required for the quiescent and migratory properties of naive T cells. Statins, a class of HMG-CoA reductase inhibitors, display pleiotropic immunomodulatory effects that are independent of their lipid-lowering capacity and may be beneficial as therapeutic agents for T cell-mediated inflammatory diseases. Statins upregulate KLF2 expression in endothelial cells, and this activity is associated with an antiinflammatory phenotype. We therefore hypothesized that the immunomodulatory effects of statins are due, in part, to their direct effects on T cell KLF2 gene expression. Here we report that lipophilic statin treatment of mouse and human T cells increased expression of KLF2 through a HMG-CoA/ prenylation-dependent pathway. Statins also diminished T cell proliferation and IFN-γ expression. shRNA blockade of KLF2 expression in human T cells increased IFN-γ expression and prevented statin-induced IFN-γ reduction. In a mouse model of myocarditis induced by heart antigen-specific CD8 + T cells, both statin treatment of the T cells and retrovirally mediated overexpression of KLF2 in the T cells had similar ameliorating effects on disease induction. We conclude that statins reduce inflammatory functions and pathogenic activity of T cells through KLF2-dependent mechanisms, and this pathway may be a potential therapeutic target for cardiovascular diseases.

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Marine-derived Trichoderma sp. TPU199 (cf. T. brevicompactum) produced gliovirin (1), pretrichodermamide A (2), and trichodermamide A (3) in a freshwater medium. Compounds 1 and 2 are rare epidithiodiketopiperazines possessing an unusual disulfide linkage. In the seawater medium, the strain biosynthesized the 5-chloro-5-deoxy derivatives (4 and 5) of 3 and 2. The production of 5 was proportional to the concentration of seawater (NaCl). Therefore, 5-bromo-5-deoxy (6) and 5-deoxy-5-iodo (7) derivatives were biosynthesized in the freshwater media supplemented with NaBr and NaI, respectively. The structure of a new iodo derivative (7) was elucidated on the basis of its spectroscopic data.

Three new N-methyladenine-containing diterpenes, 2-oxoagelasines A (1) and F (2) and 10-hydro-9-hydroxyagelasine F (3), were isolated from the Okinawan marine sponge Agelas nakamurai Hoshino together with eight known agelasine derivatives, 2-oxoagelasine B (4), agelasines A (5), B (6), D (7), E (8), F (9), and G (10), and ageline B (11). The structures of 1-3 were assigned on the basis of their spectroscopic data and their comparison with those of the literature. Compounds 3 and 5-11 inhibited the growth of Mycobacterium smegmatis with inhibition zones of 10, 14, 15, 18, 14, 20, 12, and 12 mm at 20 μg/disc, respectively. All compounds were inactive (IC50 > 10 μM) against Huh-7 (hepatoma) and EJ-1 (bladder carcinoma) human cancer cell lines. Three 2-oxo derivatives (1, 2, and 4) exhibited markedly reduced biological activity against M. smegmatis. Moreover, compound 10 inhibited protein tyrosine phosphatase 1B (PTP1B) activity with an IC50 value of 15 μM.