Statins modulate IFN-gamma induced HLA-DR expression on intestinal epithelial cells

Abstract

Aim: Statins have been shown to attenuate IFN-γ stimulated HLA-DR expression on various cells types. There are no reports investigating effects of statins on intestinal epithelial cells (IECs). In this study we analyse the influence of statins on induced HLA-DR expression on IECs and evaluate toxic effects on these cells. Methods: HT29 cells were grown unstimulated or stimulated with hrIFN-γ (50U/ml) for 72h. Cells were simultaneously incubated with atorvastatin (0–40µM) or simvastatin (0–40µM). Co-incubation with mevalonic acid (100–400µM) served to identify statin specific effects. Cell surface expression of HLA-DR, cell proliferation rates and viability using propidium iodide staining of unfixed or ethanol fixed cells were assessed by flow cytometry. Results: HLA-DR expression, constitutively absent on HT29 cells, was markedly upregulated by IFN-γ. Ator- (0.1–10.0µM) as well as simvastatin (0.1–3.0µM) reduced IFN-γ stimulated HLA-DR expression on HT29 cells. The effect was most pronounced at 10.0µM for atorvastatin and 3.0µM for simvastatin. Higher concentrations of both statins were less effective in lowering IFN-γ induced HLA-DR and even further increased the induced HLA-DR expression. Co-incubation with mevalonic acid completely abrogated all statins effects, thus indicating the decrease and exacerbation of HLA-DR to be mediated by the inhibition of HMG-CoA reductase action. Except of simvastatin used at 40µM, ator- and simvastatin did not affect the proliferation and viability of HT29 cells. Summary: Low concentrations of Atorvastatin and Simvastatin reduce IFN-γ mediated HLA-DR expression on HT29 cells. Unexpectedly, higher concentrations of these statins not only seemed to be less effective in attenuating HLA-DR stimulation but they even further increased the effects of IFN-γ. Our results indicate that the effects observed are not related to toxic properties of statins on HT29 cells. Conclusion: The immunmodulatory action of statins on IECs and other immunocompetent cells may be used as antiinflammatory tool in therapeutic strategies for inflammatory bowel diseases. However increased HLA-DR expression on IECs due to high concentrations of statins may be in part responsible for gut associated side effects after statin medication.