FK506 and rapamycin modulate the functional activities of human peripheral blood eosinophils.
Numerous studies suggest that eosinophils may play a role in the inflammatory process of various diseases. Eosinophils are potent effectors of a variety of end-stage inflammatory activities. In addition, eosinophils are highly capable of synthesizing several cytokines which can stimulate the inflammatory responses of other cell types. Eosinophils are also responsive to a number of cytokines in that their in vitro survival as well as their effector functions can be enhanced by various cytokines. Finally, it is well established that the immunosuppressive drugs, FK506 and rapamycin, can inhibit the activation of T cells and mast cells. In the present study, the effects of FK506 and rapamycin on the activities of human peripheral blood eosinophils were investigated. It was first shown that human peripheral blood eosinophils upon stimulation with the calcium ionophore A23187 produced significant amounts of the cytokines, GM-CSF and IL3. FK506 was found to inhibit the synthesis of IL3 and GM-CSF, whereas rapamycin failed to suppress the cytokine production of eosinophils. Since FK506 and rapamycin are structurally related, the ability of rapamycin to reverse the FK506-mediated inhibition on cytokine production of eosinophils was next examined. It was observed that a 250-fold excess of rapamycin was required to antagonize the suppressive effects of FK506 on the cytokine secretion mediated by eosinophils. The capacity of rapamycin to alter the in vitro IL5-mediated survival of eosinophils was also studied. The results of this study demonstrated that rapamycin was effective in reducing the ability of IL5 to maintain the survival of eosinophils in culture; by contrast, FK506 had minimal effects on the IL5-mediated survival of eosinophils. In conclusion, the effects of FK506 and rapamycin on the activities of eosinophils appear to parallel those of mast cells and T cells. Hence, it is possible that FK506 and rapamycin might be acting on signal pathways or molecules that are shared by eosinophils, mast cells as well as T cells. Moreover, these findings suggest that both FK506 and rapamycin can potentially interfere with the capacity of eosinophils to engage in interactive activities that may contribute to the chronicity of inflammatory diseases such as asthma.
Hom
J T
JT
Department of Pulmonary and Leukotriene Research, Lilly Research Laboratories, Indianapolis, Indiana 46285.
Estridge
T
T
D000001:Calcimycin / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis*; D004804:Eosinophils / Q000187:drug effects*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007377:Interleukin-3 / Q000096:biosynthesis; D015848:Interleukin-5 / Q000502:physiology; D011090:Polyenes / Q000494:pharmacology*; D020123:Sirolimus; D016559:Tacrolimus / Q000494:pharmacology*
D016207:Cytokines; D007166:Immunosuppressive Agents; D007377:Interleukin-3; D015848:Interleukin-5; D011090:Polyenes; D000001:Calcimycin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020123:Sirolimus; D016559:Tacrolimus