Zidovudine (AZT) treatment suppresses granulocyte-monocyte colony stimulating factor receptor type alpha (GM-CSFR alpha) gene expression in murine bone marrow cells.
In vitro exposure of murine bone marrow cells to increasing concentrations of zidovudine (AZT, 0.1-50 microM) had a concentration dependent suppressive effect on the growth of granulocyte-monocyte colony forming unit (CFU-GM) derived colonies. In our previous published study, the mechanism of AZT-induced suppression of erythroid colony forming unit (CFU-E) derived colonies was linked to a decrease in erythropoitin receptor (Epo-R) gene expression. In this study, we have observed that AZT exposure also induced a concentration dependent suppressive effect (35-90%) on GM-CSF receptor type alpha (GM-CSFR alpha) gene expression. The suppression of GM-CSFR alpha mRNA expression was specific, since AZT caused a much lower decrease (15-22%) on the IL-3 receptor type alpha (IL-3R alpha) message level, and had an insignificant effect on glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and c-myc message levels. Erythropoietin (Epo) therapy has been used for reversal of AZT induced erythroid toxicity. Exposure to increasing concentrations (10-500 U/ml) of GM-CSF was unable to override the suppressive effect of AZT on CFU-GM derived colonies, however, treatment in combination with IL-3 (10-250 U/ml) ameliorated the suppressive effects of AZT on CFU-GM and on GM-CSFR alpha and IL-3R alpha gene expression. These findings suggest a mechanism via which AZT may suppress granulocyte-monocyte specific differentiation in murine bone marrow cells. These data also suggest that a combination of GM-CSF and IL-3 may be a superior therapeutic intervention for AZT-induced neutropenia.
Chitnis
Shilpa
S
Department of Pharmacology, Tulane University Health Sciences Center, New Orleans, LA 70112-2699, USA.
Mondal
Debasis
D
Agrawal
Krishna C
KC
D000818:Animals; D019380:Anti-HIV Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000633:toxicity; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D016373:DNA, Antisense / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D007377:Interleukin-3 / Q000494:pharmacology; D008297:Male; D051379:Mice; D009503:Neutropenia / Q000139:chemically induced / Q000517:prevention & control; D012313:RNA / Q000494:pharmacology; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015215:Zidovudine / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000633:toxicity
D019380:Anti-HIV Agents; D016373:DNA, Antisense; D007377:Interleukin-3; C034477:RNA primers; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D015215:Zidovudine; D012313:RNA; D016178:Granulocyte-Macrophage Colony-Stimulating Factor