Psoriasis is caused, at least in part, by the immune system mistakenly attacking healthy skin cells
3. Anti-Inflammation and Immunoregulatory Effect of Artemisinin
3.1. In Vitro Immunosuppressive Activity
T cells play pivotal role in acquired immune reaction, which includes three fundamental steps [18, 19]. First, TCR cross-linking drives T cells from G0 to G1 transition and subsequent secretion of T cell growth factor IL-2 and expression of high-affinity receptor IL-2Rα chain (CD25). Second, through autocrine/paracrine proliferative loop, IL-2 induces clone expansion and maintains survival of activated T cells. Third, after successful clearance of the pathogen, the stimulus for cytokines production is lost and activated T cells thus will undergo apoptosis. However, in autoimmune diseases, due to the persistence of autoantigen, autoreactive T cells will be activated and survive better. Autoreactive T cell proliferation is involved in the pathogenesis of various autoimmune diseases, such as rheumatoid arthritis (RA) and multiple sclerosis (MS) [20, 21]. Artemether is a potent antimalarial drug . In 2007, Wang et al. found artemether significantly suppressed the proliferation and IL-2 and interferon-γ (IFN-γ) production of T cells triggered by TCR engagement . Artemether significantly inhibited TCR engagement-triggered MAPKs signaling pathway including phosphorylation of ERK1/2, Jnk, and P38. Authors further dissected that artemether majorly affected the function of T cells, rather than the antigen-presenting cells (APCs) to exert the immunosuppressive effects.
In recent years, by inserting new groups to the parent structure of artemisinin, Li from SIMM synthesized a series of artemisinin derivatives with higher water solubility and lower toxicity [23–25]. The new compounds were screened for in vitro immunosuppressive activity, majorly focused on suppressing T cell activation. SM735, one of artemisinin derivatives developed by Li group, substantially inhibited the proliferation and IFN-γ production of mitogen Con A-stimulated splenocytes . It also significantly suppressed the IL-12, IFN-γ, and IL-6 productions from LPS-stimulated splenocytes. SM934 and SM905 were recently synthesized derivatives by Li group in SIMM [23, 25]. Similar to SM735, the studies in Zuo group in SIMM found SM905 possessed potent immunoregulatory properties [5–7].
However, SM934 is quite distinct . Similar to SM905 and artemether, in vitro, SM934 significantly inhibited the proliferation and IFN-γ production of splenocytes or purified CD4+ T cells induced by mixed lymphocyte reaction (MLR) or TCR cross-linking. In sharp contrast to all of SM905, SM735, and artemether, SM934 exerted no influence on IL-2 production and CD25 upregulation of T cells but could remarkably suppress IL-2-mediated proliferation and survival of activated T cells, which might be the consequence of blocking IL-2-induced phosphorylation of Akt. In addition, through combined staining of CD69 and annexin V, SM934 was found to preferentially promote activated T cells into early apoptosis, leaving resting T cells untouched.
Moreover, there are also studies suggesting that artemisinin derivatives will bind to calmodulin to inhibit phosphodiesterase activity, which causes the increase of intracellular cAMP level, and thus to exert the immunosuppressive activity [26, 27].