Effects of glucocorticoids and cyclosporine on IL-2 and I kappa B alpha mRNA expression in human peripheral blood mononuclear cells.
To evaluate molecular mechanisms that might account for the heterogeneity in the in vitro responsiveness of individual subjects' peripheral blood mononuclear cells (PBMC) to immunosuppressive drugs, the authors quantitated in normal human cells the suppressive effects of the glucocorticoids prednisolone and methylprednisolone and of cyclosporine on interleukin-2 (IL-2) mRNA expression and IL-2 production, as well as the stimulatory effect of these drugs on IkappaBalpha mRNA expression. As expected, cyclosporine was significantly more suppressive than either glucocorticoid of IL-2 mRNA expression and IL-2 production by mitogen-stimulated PBMC, with variable degrees of inhibition in cells from individual subjects. The authors confirmed in human PBMC the stimulation of IkappaBalphamRNA expression by the glucocorticoid reported by others in HeLa and transfected Jurkat cell lines. In addition, the authors observed a stimulatory effect on IkappaBalpha mRNA expression by cyclosporine as well in 8 of 10 PBMC preparations studied, suggesting a possible role of calcineurin in the regulation of IkappaBalpha production. Interindividual variability in the intracellular mechanisms of action, possibly based on molecular polymorphisms, might be one factor contributing to differences among patients in their clinical responses to treatment with such drugs.
Briggs
W A
WA
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Han
S H
SH
Miyakawa
H
H
Burdick
J F
JF
Kwon
H M
HM
D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D020672:I-kappa B Proteins; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D012333:RNA, Messenger / Q000096:biosynthesis*
D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D020672:I-kappa B Proteins; D007166:Immunosuppressive Agents; D007376:Interleukin-2; C000606204:NFKBIA protein, human; D012333:RNA, Messenger; D000072000:NF-KappaB Inhibitor alpha; D016572:Cyclosporine