Rapamycin inhibits aldolase A expression during human lymphocyte activation.
Rapamycin (RAPA) strongly inhibits lymphocyte activation and proliferation, but does not affect most of the activation-related gene expression at the mRNA level. In order to understand the mechanism of action of RAPA and to gain further insights in lymphocyte signalling which is impaired by RAPA, we screened for RAPA-sensitive genes using differential hybridization. The expression of human aldolase A gene was found to be inducible during T and B cell activation, and the induction was repressed by RAPA at both the mRNA and enzymatic levels. The other two important immunosuppressants, cyclosporin A and FK506, also inhibited the mitogen-induced upregulation. However, none of these three drugs inhibited the constitutive expression. There was no fluctuation of aldolase A expression during the cell cycle, and RAPA failed to block the first cell cycle after synchronization in Jurkat cells. However, the second cycle was hampered by RAPA, and this was correlated with the inhibition of aldolase A expression during this later stage. Since aldolase A is a key enzyme in glycolysis and lymphocytes mainly depend on glycolysis for energy supply, the data from this study suggest that aldolase A might be one of the downstream targets of RAPA. The inhibition of the enzyme upregulation might deprive the cells of additional supply of energy, and prevent the cells from entering an optimal status for proliferation.
Laboratory of Transplantation Immunology, Louis-Charles Simard Research Center, Notre-Dame Hospital, Montreal, Quebec, Canada.
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Wang
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Luo
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Perks
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Wu
D016572:Cyclosporine / Q000494:pharmacology; D005634:Fructose-Bisphosphate Aldolase / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D010835:Phytohemagglutinins / Q000494:pharmacology; D011090:Polyenes / Q000494:pharmacology*; D020123:Sirolimus; D016559:Tacrolimus / Q000494:pharmacology
D007166:Immunosuppressive Agents; D007376:Interleukin-2; D010835:Phytohemagglutinins; D011090:Polyenes; D015847:Interleukin-4; D016572:Cyclosporine; D005634:Fructose-Bisphosphate Aldolase; D020123:Sirolimus; D016559:Tacrolimus