The multifunctional role of mTOR in innate immunity: implications for transplant immunity.
The mammalian target of rapamycin (mTOR) is an evolutionary conserved serine-threonine kinase that senses various environmental stimuli in most cells primarily to control cell growth. Restriction of cellular proliferation by mTOR inhibition led to the use of mTOR inhibitors as immunosuppressants in allogeneic transplantation as well as novel anticancer agents. However, distinct inflammatory side effects such as fever, pneumonitis, glomerulonephritis or anemia of chronic disease have been observed under this treatment regime. Apart from the mere cell-cycle regulatory effect of mTOR in dividing cells, recent data revealed a master regulatory role of mTOR in the innate immune system. Hence, inhibition of mTOR promotes proinflammatory cytokines such as IL-12 and IL-1beta, inhibits the anti-inflammatory cytokine IL-10 and boosts MHC antigen presentation via autophagy in monocytes/macrophages and dendritic cells. Moreover, mTOR regulates type I interferon production and the expression of chemokine receptors and costimulatory molecules. These results place mTOR in a complex immunoregulatory context by controlling innate and adaptive immune responses. In this review, we discuss the clinical consequences of mTOR-inhibitor therapy and aim to integrate this recent data into our current view of the molecular mechanisms of clinically employed mTOR inhibitors and discuss their relevance with special emphasis to transplantation.
Clinical Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University Vienna, Vienna, Austria. marcus.saemann@meduniwien.ac.at
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Säemann
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Haidinger
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Hecking
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Hörl
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D000818:Animals; D001343:Autophagy / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000502:physiology; D017563:Lung Diseases, Interstitial / Q000139:chemically induced; D008264:Macrophages / Q000276:immunology; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D015427:Reperfusion Injury / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology; D020123:Sirolimus / Q000009:adverse effects / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D047908:Intracellular Signaling Peptides and Proteins; D018799:Intercellular Adhesion Molecule-1; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus