Effects of Atorvastatin on T‐Cell Activation and Apoptosis in Systemic Lupus Erythematosus and Novel Simulated Interactions With C‐Reactive Protein and Interleukin 6

Abstract

Objective We study activation of T helper 17 (Th17) and regulatory T (Treg) cells and induction of apoptosis in cells from patients with systemic lupus erythematosus (SLE) compared with controls and effects of atorvastatin and its simulated interactions with other compounds. Methods Mononuclear cells from 10 patients with SLE and 10 controls were cultured in conditions that induce Th17 and/or Treg cell polarization and/or apoptosis and were studied by FACScan. Gene expression was determined by quantitative real‐time reverse transcription–polymerase chain reaction. Cytokines in plasma were determined by enzyme‐linked immunosorbent assay. The Search Tool for Interactions of Chemicals (STITCH) was used to retrieve information regarding the binding properties of atorvastatin. Results Among patients with SLE, the proportion of Th17 (CD4+IL17+) cells was higher compared with controls after activation, with Th17 or Treg polarizing cytokines, phorbol myristate acetate, and ionomycin. In contrast, Treg cells (CD4+CD25+CD127dim/−) frequencies were lower. CD95 stimulation induced relatively more apoptosis in Treg cells and less in Th17 cells, as compared with controls. Addition of atorvastatin normalized Th17/Treg cell balance and apoptosis induction. Accordingly, the ratio of RORC/FoxP3 decreased in patients with SLE. Interleukin 17 and interleukin 6 (IL‐6) levels were increased in patients with SLE. Atorvastatin interacted strongly with C‐reactive protein (CRP) and also significantly with IL‐6. Conclusion There is a higher proportion of Th17 cells and a lower proportion of Treg cells in patients with SLE after activation. Th17 cells were more resistant than Treg cells to CD95‐induced apoptosis in SLE. Atorvastatin normalized these effects. Our findings reveal a novel mechanism behind the imbalance of Th17/Treg cells with implications for treatment in SLE. We determine for the first time simulated interaction between atorvastatin, CRP, and IL‐6, implying a novel role of atorvastatin.

A Synbiotic Ameliorates Con A‐Induced Autoimmune Hepatitis in Mice through Modulation of Gut Microbiota and Immune Imbalance

“…Most scholars emphasize the importance of CD4+ T cell in the development of AIH disease. IL‐17A is mainly produced by the pro‐inflammatory Th17 cells, which are closely associated with the pathogenesis of autoimmune disorders, such as AIH, [ 35 ] systemic lupus erythematosus, [ 36 ] and multiple sclerosis. [ 37 ] Pathogenic Th17 cells have been functionally defined according to their capacity to induce severe disease in models of autoimmunity.…”

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“…Th17 cells are a proinflammatory subgroup of Th cells and play a crucial role in the pathogenesis of autoimmune diseases. The powerful proinflammatory activity of Th17 cells may lead to many pathological features of SLE, such as induction of vascular inflammation, leukocyte recruitment, B cell activation, and the production of autoantibodies 27 . A large number of studies have shown that the number of Th17 cells and IL‐17A level in the peripheral blood of SLE patients have increased, and the upregulation of Th17 cells has also been found in the skin lesions, lungs, and kidneys of these patients 28 .…”

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