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: Another Mediator in Neural-Emerging Immune System through Tac1 Expression in Bone Marrow Stromal Cells1
* Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey, Newark, NJ 07107; and
Department of Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103
Stromal cell-derived growth factor-1
(SDF-1) is a member of the CXC chemokines and interacts with the G protein, seven-transmembrane CXCR4 receptor. SDF-1 acts as a chemoattractant for immune and hemopoietic cells. The Tac1 gene encodes peptides belonging to the tachykinin family with substance P being the predominant member. Both SDF-1 and Tac1 peptides are relevant hemopoietic regulators. This study investigated the effects of SDF-1 on Tac1 expression in the major hemopoietic supporting cells, the bone marrow stroma, and addresses the consequence to hemopoiesis. Reporter gene assays with the 5' flanking region of Tac1 showed a bell-shaped effect of SDF-1 on luciferase activity with 20 ng/ml SDF-1 acting as stimulator, whereas 50 and 100 ng/ml SDF-1 acted as inhibitors. Gel shift assays and transfection with wild-type and mutant I
B indicate NF-B as a mediator in the repressive effects at 50 and 100 ng/ml SDF-1. Northern analyses and ELISA showed correlations among reporter gene activities, mRNA (
-preprotachykinin I), and protein levels for substance P. Of relevance is the novel finding by long-term culture-initiating cell assays that showed an indirect effect of SDF-1 on hemopoiesis through substance P production. The results also showed neurokinin 1 and not neurokinin 2 as the relevant receptor. Another crucial finding is that substance P does not regulate the production of SDF-1 in stroma. The studies indicate that SDF-1 levels above baseline production in bone marrow stroma induce the production of substance P to stimulate hemopoiesis. Substance P, however, does not act as autocrine stimulator to induce the production of SDF-1. This study adds SDF-1 as a mediator within the neural-immune-hemopoietic axis.
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1 This work was supported by grants from the Department of Defense and the University Hospital Cancer Center, University of Medicine and Dentistry of New Jersey, New Jersey Medical School. This work was performed in partial fulfillment for a Ph.D. thesis by K.E.C. and was done at the Department of Medicine, Division of Hematology/Oncology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103.
2 Address correspondence and reprint requests to Dr. Pranela Rameshwar, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Medical Science Building, Room E-579, 185 South Orange Avenue, Newark, NJ 07103. E-mail address: rameshwa{at}umdnj.edu
3 Abbreviations used in this paper: PPT-I, preprotachykinin I; Alk Phos, alkaline phosphatase; BM, bone marrow; -gal, -galactosidase; HSC, hemopoietic stem cell; LTC-IC, long-term culture-initiating cell; NK, neurokinin; SDF, stromal-derived growth factor; SP, substance P.
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