Rapamycin inhibits the in vitro release of soluble interleukin-2 receptor by activated peripheral blood mononuclear cells (PBMC) independently of the mode of activation.
In the present study we compared the effect of rapamycin to that of CsA on the in vitro responses of lectin (PHA), phorbol-ester (PMA) and CA2+ ionophore (ionomycin)-activated peripheral blood mononuclear cells by measuring the release of soluble IL-2R (sIL-2R), high levels of which have been detected in clinical syndromes characterized by an ongoing immune activation. PHA was the stimulant associated with high sIL-2R release, whereas ionomycin-induced sIL-2R release only exceeded the background response and the sensitivity of the ELISA kit. The highest sIL-2R release, however, was obtained when PMA was used in combination with either PHA or ionomycin. Rapamycin inhibited the release of sIL-2R in response to all activators, whereas CsA only abolished the ionomycin-induced sIL-2R release. In parallel experiments rapamycin inhibited cell proliferation in response to all stimulants with the exception of PMA/ionomycin, whereas CsA inhibited all proliferation. Our study clearly shows that for optimal sIL-2R release both Ca+ and protein kinase C-triggered signals are required and that rapamycin has a distinct advantage over CsA in inhibiting the release of sIL-2R, which has been shown to be a reliable marker of lymphocyte activation either in vivo or in vitro.
Degiannis
D
D
Molecular Immunopathology/Histocompatibility Laboratory, Onassis Cardiac Surgery Center, Athens, Greece.
Hornung
N
N
D001711:Biotransformation / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D010703:Phorbol Esters / Q000494:pharmacology; D011090:Polyenes / Q000494:pharmacology*; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors*; D020123:Sirolimus
D007166:Immunosuppressive Agents; D007476:Ionophores; D010703:Phorbol Esters; D011090:Polyenes; D015375:Receptors, Interleukin-2; D015759:Ionomycin; D016572:Cyclosporine; D020123:Sirolimus