Molecular actions of sirolimus: sirolimus and mTor.
Recent therapeutic strategies to combat organ allograft rejection have focused on T-cell signaling pathways and the molecules that comprise them. The macrolide antibiotic produced by the bacterium Streptomyces hygroscopicus, known as sirolimus or rapamycin, has shown great therapeutic potential in the transplant setting. Sirolimus alone or in combination with other immunosuppressive agents can block acute rejection, chronic graft destruction, and promote permanent allograft acceptance. Sirolimus targets a unique serine-threonine kinase, mammalian target of rapamycin (mTor), which plays a key role in mitogenic and nutritional cells signals. Within T cells, mTor regulates a number of proteins likely dependent on T cell growth factors such as interleukin 2. This review is focused on the molecular mechanisms by which mTor may regulate T-cell signaling cascades and affect T-cell responsiveness, and how sirolimus likely uncouples this activity.
Kirken
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Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA. robert.a.kirken@uth.tmc.edu
Wang
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D004789:Enzyme Activation; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D020123:Sirolimus / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000276:immunology; D058570:TOR Serine-Threonine Kinases
D007166:Immunosuppressive Agents; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus