HEMATOPOIETIC REGULATION MEDIATED BY INTERACTIONS AMONG THE NEUROKININS AND CYTOKINES

This review summarizes the current data regarding the mechanisms by wh ich two mammalian neurokinins (tachykinins), substance P (SP) and neur okinin-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 cyto kines and neurotrophic factors. In the bone marrow (BM), nerve fibers and stroma are potential sources for the PPT-I gene products. SP and N K-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 ex ert dichotomous hematopoietic effects mediated mostly by the BM stroma . SP enhances the proliferation of primitive BM stem cells and progeni tors and these effects correlate with the induction of stimulatory hem atopoietic growth factors. NK-A appears to be protective to stem cells through the induction of TGF-beta. Proliferation of myeloid progenito rs is inhibited by NK-A, effects which correlate with the induction of two suppressive factors, TGF-beta and MIP-1 alpha. Stimulation of NK- 2 leads to partial blunting of the enhanced stimulatory effects mediat ed by NK-1. Furthermore, stimulatory hematopoietic cytokines upregulat e NK-1 expression and downregulate the constitutively expressed NK-2 i n BM stroma. Together, the experimental evidence suggests that NK-A-NK -2 interactions could be a feedback to hematopoietic stimulation. Expr ession of NK-1 and NK-2 in CD34(+) cell lines and also, the presence o f SP binding sites on primary CD34(+) cells suggest that the neurokini ns could be interacting directly with BM progenitors and stem cells. I n BM stroma, cytokines and neurokinins regulate the expression of each other and also, their respective receptors. In summary, the current l iterature pertaining to hematopoietic regulation indicates the involve ment of a complex network that includes, but not exclusive of the cyto kines and neurokinins. The current models that pertain to stem cell pr oliferation and differentiation should therefore add neuropeptides to the list of hematopoietic modulators.