s-trans-trans-farnesylthiosalicylic-acid and Diabetes-Mellitus

Naturally occurring regulatory T cells (Treg) driven by their transcriptional controller Foxp3 are compromised in immune-mediated disorders and confer protection when adoptively transferred. We examined the Ras-inhibitory effect on functional determinants of Treg in vivo and in vitro. Ras was inhibited in Jurkat T cells by transfection with a dominant-negative form of Ras, or by shRNA for N-Ras, K-Ras, and H-Ras, or by farnesylthiosalycylic acid, a small-molecule inhibitor. Except for H-Ras transduction with shRNA, each inhibitory mode increased expression of Foxp3 and nuclear factor of activated T cell proteins, and surface expression of CD25. Ras inhibition in PBMC and spleen-derived lymphocytes reproduced these findings. The heightened Foxp3 expression reflected both increased basal cellular protein and peripheral conversion of non-Treg to Treg. Ras inhibition enhanced Treg-induced suppression; thus, when adoptively transferred to mice, Ras-inhibited Treg reduced the incidence of diabetes. Inhibition of Foxp3 by respective siRNA reversed the enhancement. Thus, inhibition of the N- or K-Ras isoform triggers an anti-inflammatory effect by up-regulating, via Foxp3 elevation, the numbers and functional suppressive properties of Treg.

Topics: Adoptive Transfer; Animals; CD4-Positive T-Lymphocytes; Cell Differentiation; Cell Nucleus; Coculture Techniques; Diabetes Mellitus; Enzyme Inhibitors; Farnesol; Forkhead Transcription Factors; Humans; Interleukin-2 Receptor alpha Subunit; Jurkat Cells; Leukocytes, Mononuclear; Lymphocyte Activation; Mice; Mice, Inbred BALB C; NFATC Transcription Factors; Proto-Oncogene Proteins p21(ras); RNA Interference; Salicylates; Spleen; T-Lymphocytes; T-Lymphocytes, Regulatory; Transfection; Up-Regulation