ReviewMechanisms of action of cyclosporine
Section snippets
Action on the calcineurin/NFAT pathway
Cyclosporine (cyclosporin A, CsA), a neutral lipophilic cyclic undecapeptide isolated from the fungus Hypocladium inflatum gams, has been widely used for the treatment of allograft rejection and graft-vs.-host disease since Borel et al. (1976) reported its immunosuppressive activity. Early biological studies revealed that CsA inhibits T cell activation by blocking the transcription of cytokine genes, including those of IL-2 and IL-4 Kronke et al., 1984, Herold et al., 1986, Granelli-Piperno,
Action on JNK and p38 signaling pathways
Transcriptional activation of the IL-2 gene requires cooperative interaction of several transcription factors, including AP-1, NF-κB, and NFAT (Crabtree, 1989). It has been shown that CsA affects the activities of AP-1 and NF-κB in addition to NFAT, implying the presence of another target(s) of CsA as well as the calcineurin/NFAT pathway (Rincon and Flavell, 1994, Mattila et., 1990). It has also been shown that CsA can inhibit an antigen-specific and Ca2+-independent response (Metcalfe et al.,
Other effects of CsA
Despite being highly efficacious for prevention of organ transplant rejection, the use of CsA as an immunosuppressant is limited by severe side effects including nephrotoxicity, neurotoxicity, and hepatotoxicity (Kahan, 1989). CsA has been shown to induce the synthesis of TGF-β in vitro and in vivo Li et al., 1991, Khanna et al., 1994, Wolf et al., 1995, Shihab et al., 1996. Several studies have suggested the involvement of TGF-β in the progression of renal diseases Klahr et al., 1995, Border
Newly identified proteins with putative immunosuppressive activity
Recent studies have identified several proteins which exhibit functions similar to CsA. Sun et al. (1998) identified a novel calcineurin-binding protein named Cabin1, which binds to and inhibits the phosphatase activity of calcineurin. Cabin1 is widely expressed in a variety of tissues and cells, including the spleen and leukocytes. Since Cabin1, when over-expressed, inhibits dephosphorylation of NFAT protein and blocks the transcriptional activation of IL-2 reporter gene during T cell
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