Stromal derived growth factor-1α:: Another mediator in neural-emerging immune system through Tac1 expression in bone marrow stromal cells

Stromal cell-derived growth factor-1 alpha (SDF-1 alpha) is a member of the CXC chemokines and interacts with the G protein, seven-transmembrane CXCR4 receptor. SDF-1 alpha 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 alpha and Tac1 peptides are relevant hemopoietic regulators. This study investigated the effects of SDF-1 alpha 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 alpha on luciferase activity with 20 ng/ml SDF-1 alpha acting as stimulator, whereas 50 and 100 ng/ml SDF-1 alpha acted as inhibitors. Gel shift assays and transfection with wild-type and mutant I kappa B indicate NF-kappa B as a mediator in the repressive effects at 50 and 100 ng/ml SDF-1 alpha. Northern analyses and ELISA showed correlations among reporter gene activities, mRNA (beta-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-la 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 Phi in stroma. The studies indicate that SDF-1 alpha 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 alpha. This study adds SDF-1 alpha as a mediator within the neural-immune-hemopoietic axis. The Journal of Immunology, 2007, 178: 2075-2082.