Evidence that rapamycin has differential effects of IL-4 function. Multiple IL-4 signaling pathways and implications for in vivo use.
The immunosuppressive drug rapamycin, which inhibits the response of T cells to growth-promoting lymphokines, has been considered to act as a general inhibitor of cytokine action. Our investigations into the effect of rapamycin on human IL-4, a cytokine controlling B and T cell function, show this not to be the case. Unexpectedly, rapamycin actually synergized with IL-4 in both the upregulation of CD23 expression and the down-regulation of the type II (p75) TNF receptor, while in the same B cell line, rapamycin simultaneously inhibited the IL-4-dependent production of TNF alpha and beta. These results raise the possibility that multiple IL-4 signaling pathways may be responsible for the pleiotropic effects of IL-4, and have important implications for both the experimental and possible clinical in vivo use of rapamycin as a selective immunosuppressant.
Taylor-Fishwick
D A
DA
Kennedy Institute of Rheumatology, Hammersmith, London, United Kingdom.
Kahan
M
M
Hiestand
P
P
Ritter
M A
MA
Foxwell
B M
BM
D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008233:Lymphotoxin-alpha / Q000378:metabolism; D011090:Polyenes / Q000494:pharmacology*; D017455:Receptors, IgE / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology*; D020123:Sirolimus; D013268:Stimulation, Chemical; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology; D016559:Tacrolimus / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D007166:Immunosuppressive Agents; D008233:Lymphotoxin-alpha; D011090:Polyenes; D017455:Receptors, IgE; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus