Feedback regulation during immune cell development by Preprotachykinin-I (PPT-I) peptide fragment. Implications for endogenous endopeptidases

Anterograde-retrograde transport of soluble products mediate bidirectional neural-hematopoietic crosstalk. Several of these soluble mediators are labile implying that their release in target tissues can only lead to paracrine functions. The distance between the communicating systems, nervous and bone marrow (BM), brings into question the extent of anterograde-retrograde crosstalk. In particular, during urgent need for immune cells. We hypothesize that signals to the BM by neurotransmitters lead to complex responses so that the source of the neurotransmitters are switched to the BM stroma. Substance P (SP), the major PPT-I peptide, induces proliferation of early and late immune cell progenitors. This stimulatory role of SP leaves a disturbing question of stem cell depletion. We alluded that the other PPT-I peptide, NK-A, could be a negative feedback. Since BM cells express endogenous endopeptidases that can utilize SP as a substrate to produce SP_(1-4), we determined whether SP_(1-4) can exert negative feedback. Using clonogenic assays, we have found that SP_(1-4), through the NK-1 receptor, inhibits myelopoiesis. These effects are partly indirect through the production of prostaglandins, TNF-α, TGF-β and IFN-γ in BM cells. We have screened a random dodecapeptide library for SP_(1-4) interacting peptides. Molecular modeling with the peptide sequences will bring into focus SP_(1-4)-NK-1 interactions and ultimately, add to the hematopoietic network which should encompass cytokines, neuropeptides and endopeptidases.