Tanshinone I inhibits the functions of T lymphocytes and exerts therapeutic effects on delayed-type hypersensitivity reaction via blocking STATs signaling pathways

Abstract

Delayed-type hypersensitivity (DTH) reactions are a kind of chronic inflammatory diseases initiated by antigens and antigen-specific T cells. Currently, the therapy of DTH reactions is limited by the poor curative effects and serious adverse reactions of existing agents. In this study, we investigated the regulatory effects of tanshinone Ⅰ, a natural compound isolated from Salvia miltiorrhiza, on the functions of multiple immune cells and its therapeutic effects on DNFB-induced DTH reaction, and then explored its immunosuppressive mechanisms. The results showed that tanshinone Ⅰ at 5–20 μM moderately inhibited the activation of macrophages and dendritic cells, but did not weaken the activation of neutrophils. Tanshinone Ⅰ at 1–4 μM intensively suppressed the activation, proliferation, and differentiation of CD4⁺ and CD8⁺ T cells, and slightly affected the functions of B cells. Tanshinone Ⅰ administration markedly alleviated the edema, inflammatory response, and the infiltrations of CD4⁺ T cells, CD8⁺ T cells, and CD11b⁺ cells in ear tissues of mice which were induced DTH reactions by DNFB. Transcriptome analysis revealed that tanshinone Ⅰ strongly inhibited CD4⁺ T cells to express genes involving in cell proliferation, metabolism, activation, and differentiation. Furthermore, immunoblotting analysis showed that tanshinone Ⅰ selectively inhibited the phosphorylation of STAT3 and STAT5 in CD4⁺ T cells stimulated by anti-CD3e and anti-CD28 antibodies or IL-2. Collectively, tanshinone Ⅰ can strongly inhibit the functions of T lymphocytes, exert therapeutic effects on DTH reaction by blocking STATs signaling pathways, and has potential to be developed into therapeutic drug for DTH reactions.