Trichomide A, a Natural Cyclodepsipeptide, Exerts Immunosuppressive Activity against Activated T Lymphocytes by Upregulating SHP2 Activation to Overcome Contact Dermatitis

Abstract

Increasing numbers of people are suffering from allergic contact dermatitis. However, the immunosuppressive drug candidate with negligible toxicity is still deficient. In the present study, we identified a natural cyclodepsipeptide named trichomide A that effectively inhibited the proliferation of activated T cells and reduced the production of proinflammatory cytokines but had almost no toxic effect on naive T cells at 0.3-3 μM. In addition, trichomide A caused G0/G1 phase arrest, suppressed the activation of AKT and STAT3, and increased the level of phosphorylated SHP2 in activated T cells in dose- and time-dependent manners. Furthermore, an in vivo experiment demonstrated that trichomide A significantly ameliorated picryl chloride (PCI)-induced contact hypersensitivity in mice. Such effects of trichomide A in the aforementioned experiments were significantly reversed by the inhibition of SHP2 activity using the SHP2-specific inhibitor PHPS1 or conditional SHP2 knockout mice in T cells, suggesting the SHP2-dependent action of trichomide A. Taken together, trichomide A showed an immunosuppressive activity against T cell-mediated immune responses both in vitro and in vivo, which has potential for the treatment of immune-related skin diseases.