IMMUNOMODULATORS AND THEIR RECEPTORS 395Although it is not chemically related to cyclosporine, tacrolimus (6.7) has a similar
mechanism of action. Tacrolimus is an immunosuppressant macrolide antibiotic
derived from Streptomyces tsukubaenis.Like cyclosporine, tacrolimus inhibits the
same cytoplasmic phosphatase, calcineurin, which catalyzes the activation of a T-cell-
specific transcription factor (NF-AT) involved in the biosyntheses of interleukins such
as IL-2. Sirolimus (6.8) is a natural product produced by Streptomyces hydroscopicus;
it blocks the ability of T cells to respond to cytokines.
Thalidomide (6.9) is another agent that alters cytokine action. Thalidomide is the
infamous drug that produced disastrous birth defects (such as phocomelia, in which the
hands or feet are attached close to the body, resembling flippers, because of very short
limbs) when administered to pregnant women. Thalidomide stimulates responsiveness
to IL-4 and IL-5 cytokine stimulation, thus favoring the TH2 subtype of cell and dis-
torting the balance between TH1 and TH2 effects. Despite its unfortunate history,
thalidomide is an effective agent, now widely used for a variety of immune-related
disorders, including leprosyandsystemic lupus erythmatosus.