Vasoactive intestinal peptide (VIP) inhibits the proliferation of bone marrow progenitors through the VPAC1 receptor.
OBJECTIVE
The cellular and molecular mechanisms of hematopoietic stimulation have been studied. However, an understanding of negative effects in the hematopoietic system remains elusive. To this end, we studied the effects of vasoactive intestinal peptide (VIP) on bone marrow (BM) progenitors.


METHODS
Different BM cell subsets were used to perform clonogenic assay for granulocytic (CFU-GM) or erythroid (BFU-E and CFU-E) progenitors with 10(-7)-10(-13) M VIP. The relevant receptor was verified with specific antagonists, or agonists, semi-quantitative RT-PCR, and chemical cross-linking studies with stromal membranes.


RESULTS
Assays performed with unfractionated mononuclear cells and enriched CD34(+) cells showed dose-dependent inhibition on BM progenitors with significant inhibition up to 10(-10) M. Nylon wool separated cells, which depleted stroma, reversed the inhibitory effects of VIP between 10 and 20%. Combined experimental evaluation indicated that the effects of VIP on BM functions are mediated through the type 1 receptor (VPAC1). VIP induced the production of TGF-beta and TNF-alpha in BM mononuclear cells and stroma. These cytokines are partly involved in reversing the suppressive effects of VIP on CFU-GM.


CONCLUSIONS
The effect of VIP on BM progenitors could be mediated through direct and indirect mechanism. Direct effects were evident by the suppressive effects of VIP on clonogenic assays with highly purified CD34(+) cells. Indirect effects were mediated through putative functions of the stromal cells and the production of TGF-beta and TNF-alpha.
Rameshwar
Pranela
P
Department of Medicine, UMDNJ-New Jersey Medical School, Newark, NJ 07103, USA. rameshwa@umdnj.edu
Gascon
Pedro
P
Oh
Hyun S
HS
Denny
Thomas N
TN
Zhu
Goafa
G
Ganea
Doina
D
D000328:Adult; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D018920:Coculture Techniques; D003114:Colony-Forming Units Assay; D003432:Cross-Linking Reagents / Q000494:pharmacology; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects; D004921:Erythropoietin / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D018922:HL-60 Cells / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D018005:Receptors, Vasoactive Intestinal Peptide / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000187:drug effects / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology*
D003432:Cross-Linking Reagents; D007377:Interleukin-3; D018005:Receptors, Vasoactive Intestinal Peptide; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D011994:Recombinant Proteins; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D004921:Erythropoietin; D014660:Vasoactive Intestinal Peptide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor