Induction of negative hematopoietic regulators by neurokinin-A in bone marrow stroma.
The tachykinins are a family of neuropeptides that share a common carboxyl terminus. Substance P (SP) and neurokinin-A (NK-A) are derived from the preprotachykinin l gene. Although SP and NK-A can bind to either NK-1, NK-2, or NK-3 receptors (R), they have preferences for NK-1R and NK-2R, respectively. We have reported that SP stimulates erythroid (E) (burst-forming unit [BFU]-E and colony-forming unit [CFU]-E) and myeloid (CFU-granulocyte-macrophage [GM]) progenitors partly through the induction of growth factors. We have now investigated the hematopoietic effects of NK-A using short-term bone marrow (BM) cultures and found that NK-A (10(-7) to 10(-12) mol/L) inhibits CFU-GM proliferation but stimulates erythroid progenitors. Release of soluble factors by the stroma appears to mediate the inhibition because direct contact with the stroma was not required. We have found that NK-A, through NK-2-like receptors induces increased levels of macrophage inflammatory protein-1 alpha (MIP-1 alpha) and transforming growth factor-beta (TGF-beta) (transcriptional and posttranscriptional) in BM stroma. Clonogenic assays with NK-A (10(-9) mol/L) and either anti-MIP-1 alpha or anti-TGF- beta 1 indicate that these cytokines partly contribute to the inhibition, suggesting that these two negative hematopoietic regulators exert part of the inhibition by NK-A on CFU-GM. The findings of two closely related neuropeptides, derived from the same gene, exerting opposite effects on myeloid colonies suggest that neuropeptides, by themselves could be important factors in hematopoietic regulation.
Rameshwar
P
P
Department of Medicine, UMDNJ-New Jersey Medical School, Newark 07103, USA.
Gascón
P
P
D000595:Amino Acid Sequence; D001549:Benzamides / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism; D001854:Bone Marrow Cells; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D054407:Chemokine CCL4; D003238:Connective Tissue / Q000187:drug effects* / Q000378:metabolism; D003864:Depression, Chemical; D015672:Erythroid Precursor Cells / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D019402:Macrophage Inflammatory Proteins; D008969:Molecular Sequence Data; D015846:Monokines / Q000378:metabolism*; D015288:Neurokinin A / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000187:drug effects*; D018041:Receptors, Neurokinin-2 / Q000187:drug effects*; D018042:Receptors, Neurokinin-3 / Q000187:drug effects*; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D001549:Benzamides; D001713:Biphenyl Compounds; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D015846:Monokines; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; D016212:Transforming Growth Factor beta; D013373:Substance P; C073839:SR 48968; D015288:Neurokinin A; C042867:spantide; C066892:CP 96345