Hematopoietic regulation mediated by interactions among the neurokinins and cytokines

This review summarizes the current data regarding the mechanisms by which two mammalian neurokinins (tachykinins), substance P (SP) and neurokinin-A (NK-A) are involved in hematopoiesis. SP and NK-A are derived from the preprotachykinin-I (PPT-I) gene which can be induced by cytokines and neurotrophic factors. In the bone marrow (BM), nerve fibers and stroma are potential sources for the PPT-I gene products. SP and NK-A interact with either of three cloned receptors, neurokinin-1 (NK-1), NK-2 or NK-3, although SP and NK-A exhibit binding preferences for NK-1 and NK-2 respectively. Through specific receptors, SP and NK-A exert dichotomous hematopoietic effects mediated mostly by the BM stroma. SP enhances the proliferation of primitive BM stem cells and progenitors and these effects correlate with the induction of stimulatory hematopoietic growth factors. NK-A appears to be protective to stem cells through the induction of TGF-beta. Proliferation of myeloid progenitors is inhibited by NK-A, effects which correlate with the induction of two suppressive factors, TGF-beta and MIP-1alpha. Stimulation of NK-2 leads to partial blunting of the enhanced stimulatory effects mediated by NK-1. Furthermore, stimulatory hematopoietic cytokines upregulate NK-1 expression and downregulate the constitutively expressed NK-2 in BM stroma. Together, the experimental evidence suggests that NK-A-NK-2 interactions could be a feedback to hematopoietic stimulation. Expression of NK-1 and NK-2 in CD34+ cell lines and also, the presence of SP binding sites on primary CD34+ cells suggest that the neurokinins could be interacting directly with BM progenitors and stem cells. In BM stroma, cytokines and neurokinins regulate the expression of each other and also, their respective receptors. In summary, the current literature pertaining to hematopoietic regulation indicates the involvement of a complex network that includes, but not exclusive of the cytokines and neurokinins. The current models that pertain to stem cell proliferation and differentiation should therefore add neuropeptides to the list of hematopoietic modulators.