Pentoxifylline and other methyl xanthines inhibit interleukin-2 receptor expression in human lymphocytes.
Addition of pentoxifylline to lymphocytes caused a dose-dependent decrease in PHA-induced interleukin-2 receptor (IL-2R) expression. Expression of IL-2R protein and mRNA were inhibited by 60% at a concentration of 1 mM. Pentoxifylline also inhibited release of IL-2R into the medium by 85%. Treatment with recombinant IL-2 (50 U/ml) did not abrogate the effect of pentoxifylline. In addition to inhibition of IL-2R expression, pentoxifylline also decreased the expression of transferrin receptors and class I MHC antigens. Pentoxifylline also inhibited cell proliferation. However, aphidicolin, an inhibitor of DNA polymerase alpha inhibited cell proliferation to the same extent as pentoxifylline, but had no effect on IL-2R expression, indicating that inhibition of cell proliferation does not necessarily lead to inhibition of IL-2R expression. The inhibitory effect on IL-2R expression was also noted with other methylxanthines, theophylline and isobutylmethylxanthine, and with dbcAMP and forskolin. The inhibitory activity of pentoxifylline was prevented by W-13, a calmodulin antagonist, but not by HA-1004, a cyclic AMP-dependent protein kinase inhibitor. This suggests that pentoxifylline might act in part through a Ca2+/calmodulin-dependent mechanism. Pentoxifylline and other methylxanthines may prove useful in delineating the biochemical pathways involved in induction and expression of cell surface receptors.
Rao
K M
KM
Geriatric Research, Education and Clinical Center, VA Medical Center, Durham, North Carolina.
Currie
M S
MS
McCachren
S S
SS
Cohen
H J
HJ
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D016590:Aphidicolin; D002147:Calmodulin / Q000502:physiology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology; D004224:Diterpenes / Q000494:pharmacology; D015395:Histocompatibility Antigens Class I / Q000032:analysis; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects*; D010431:Pentoxifylline / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D015375:Receptors, Interleukin-2 / Q000032:analysis* / Q000187:drug effects / Q000235:genetics; D011990:Receptors, Transferrin / Q000032:analysis
D002147:Calmodulin; D004224:Diterpenes; D015395:Histocompatibility Antigens Class I; D007376:Interleukin-2; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D011990:Receptors, Transferrin; D016590:Aphidicolin; D000242:Cyclic AMP; D010431:Pentoxifylline; D015056:1-Methyl-3-isobutylxanthine