A SPHINGOSINE-DERIVATIVE SUPPRESSES PRO-INFLAMMATORY RESPONSES IN THE KIDNEY THROUGH REGULATION OF NFΚB

picture of Elina Ly presenting his/her poster: A SPHINGOSINE-DERIVATIVE SUPPRESSES PRO-INFLAMMATORY RESPONSES IN THE KIDNEY THROUGH REGULATION OF NFΚB

Elina Ly , Kim-Chong Yong, Yeong-Hau H Lien, Li-Wen Lai

A SPHINGOSINE-DERIVATIVE SUPPRESSES PRO-INFLAMMATORY RESPONSES IN THE KIDNEY THROUGH REGULATION OF NFΚB

A sphingosine-derivative (DMS) has been identified which ameliorates renal ischemic reperfusion injury through the reduction in NFκB, a pro-inflammatory transcription factor. When phosphorylated, activated NFκB translocates into the nucleus to activate expression of a variety of pro-inflammatory genes. Both phosphorylated and non-phosphorylated levels of NFκB were measured in renal proximal tubular cells before and after DMS treatment by immunofluorescence staining and ArrayScan® VTI HCS reader. DMS decreased NFκB and p-NFκB nucleus intensities up to 40%, with cytosol intensities decreasing up to 23%. This decrease in nuclear translocation and activation is dose-dependent (1-5 uM) and was observed within 5 minutes, reaching a plateau at 30 minutes. Subsequent experiments were conducted to measure NFκB and p-NFκB with western blotting on DMS treated renal proximal tubular cells. Nuclear protein levels initially increase up to 100% above the vehicle control by 15 minutes. This is followed by a decrease up to 40% below the vehicle control by the end of 1 hour. This effect is also dose dependent (0.5-2.5 uM). In conclusion, our findings are consistent with the hypothesis that DMS enhances NFκB suppression in the cytosol, resulting in a reduction in NFκB nuclear translocation and activation. Studies are ongoing to further pinpoint DMS’s role in the upstream signaling pathway of NFκB activation and to develop a novel Treg-based therapy for inflammatory diseases. This research was funded by NIH grant RO1DK82718 and HHMI grant 52006942.

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