Abstract
T cells have been classified as belonging to the Th1 or Th2 subsets according to the production of defining cytokines such as IFN-γ and IL-4. The discovery of the Th17 lineage and regulatory T cells shifted the simple concept of the Th1/Th2 balance into a 4-way mechanistic pathway of local and systemic immunological activity. Clinically, the blockage of cytokine signals or non-specific suppression of cytokine predominance by immunosuppressants is the first-line treatment for inflammatory T cell-mediated disorders. Cyclosporine A (CsA) and Tacrolimus (Tac) are commonly used immunosuppressants for the treatment of autoimmune disease, psoriasis, and atopic disorders. Many studies have shown that these compounds suppress the activation of the calcium-dependent phosphatase calcineurin, thereby inhibiting T-cell activation. Although CsA and Tac are frequently utilized, their pharmacological mechanisms have not yet been fully elucidated.In the present study, we focused on the effects of CsA and Tac on cytokine secretion from purified human memory CD4+T cells and the differentiation of naïve T cells into cytokine-producing memory T cells. CsA or Tac significantly inhibited IFN-γ, IL-4, and IL-17 production from memory T cells. These compounds also inhibited T cell differentiation into the Th1, Th2, and Th17 subsets, even when used at a low concentration. This study provided critical information regarding the clinical efficacies of CsA and Tac as immunosuppressants.
Highlights
T cells were classified as Th1 or Th2 subtypes according to the production of defining cytokines such as IFN-c, IL12, and IL-4
Fluorescence profiles showed distinct cytokine productions from mature cells, and the production of all cytokines investigated here was strikingly suppressed with the addition of Cyclosporine A (CsA) or Tac, even at the lower concentration
The percentages of IFN-c+CD4+ T cells (B), IL-4+CD4+ T cells (C) or IL-17+CD4+ T cells (D) within the CD4+ T cell population were significantly suppressed with the addition of CsA or Tac
Summary
T cells were classified as Th1 or Th2 subtypes according to the production of defining cytokines such as IFN-c, IL12, and IL-4. Several autoimmune diseases, including rheumatoid arthritis (RA) and psoriasis, had been considered to be Th1-cellmediated disorders driven by a population of T cells producing inflammatory cytokines, such as IL-2, IL-12, TNF-a and interferons [1,2,3]. Many studies have shown that CsA binds to cyclophilin intracellularly to prohibit the synergistic action of Ca2+ and suppresses the activation of the calcium-dependent phosphatase calcineurin, thereby affecting the production of cytokines, such as IL2 and IFN-c [7,8]. Tacrolimus (Tac) is a widely used T-celltargeted immunosuppressant and a known calcineurin inhibitor. This macrolide from the filamentous bacterium Streptomyces tsukubaensis exerts its immunosuppressive effects by inhibiting T-cell activation, in Th1 cells. The pharmacological mechanisms of CsA and Tac have not yet been fully elucidated
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