Enhanced ability of the progenipoietin-1 to suppress apoptosis in human hematopoietic cells.
Repopulating hematopoietic cell compartments after myeloablative chemotherapy remains a key factor in a successful chemotherapy program. Modified and chimeric cytokines have been developed to help reduce inflammation, fever and hospitalization time for patients. A chimeric cytokine, progenipoietin-1 (ProGP-1), containing the G-CSF and FL receptor agonists binds both the G-CSF receptor and FLT-3. It also stimulates the growth of dendritic cells, which play an important role in immunotherapy. While in vivo effects of ProGP-1 are well described, the mechanisms by which it stimulates growth are not well understood. We have investigated the effects of ProGP-1 on prevention of apoptosis in the human hematopoietic cell line OCI-AML.5. ProGP-1 promoted cellular proliferation better than G-CSF or FL separately but stimulated proliferation similar to their co-addition as demonstrated by growth curves and [3H]-thymidine incorporation. ProGP-1 prevented apoptosis to a greater degree than G-CSF or FL alone as determined by annexin V/propidium iodide binding and TUNEL assays. ProGP-1 promoted maintenance of the mitochondrial membrane potential better than G-CSF or FL alone. In addition, Pro-GP promoted a lower redox potential as higher levels of free radicals were detected after cytokine treatment than in cytokine-deprived cells implying increased respiration. These data indicate that ProGP-1 promotes the proliferation and prevents the apoptosis of human hematopoietic cells better than FL or G-CSF alone, and to a similar extent as their co-addition. Thus, ProGP-1 can be used to repopulate certain hematopoietic cells as a single entity rather than the introduction of two different cytokines.
Saleh
Oussama A
OA
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA.
Blalock
William L
WL
Burrows
Carla
C
Steelman
Linda S
LS
Doshi
Parul D
PD
McKearn
John P
JP
McCubrey
James A
JA
D000165:Acridine Orange; D017304:Annexin A5; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D003115:Colony-Stimulating Factors / Q000378:metabolism* / Q000494:pharmacology; D004996:Ethidium; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D020287:In Situ Nick-End Labeling; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D011419:Propidium; D011994:Recombinant Proteins
D017304:Annexin A5; D003115:Colony-Stimulating Factors; D011994:Recombinant Proteins; C434603:progenipoietin-1; D016179:Granulocyte Colony-Stimulating Factor; D011419:Propidium; D004996:Ethidium; D000165:Acridine Orange