Rameshwar P, Gascón P
UMDNJ-New Jersey Medical School, Department of Medicine-Hematology, Newark 07103, USA.
Acta Haematol. 1997;98(2):59-64. doi: 10.1159/000203593.
We have been studying hematopoietic effects by the tachykinins, which like many other neuropeptides can be expressed in neural and nonneural tissues. Substance P (SP) and neurokinin-A (NK-A), members of the tachykinins are immune and hematopoietic modulators. SP and NK-A are derived from the preprotachykinin-I gene (PPT-I) through alternate splicing and posttranslational modification. In the bone marrow (BM), nerve fibers provide a source of neural SP and the stroma provides a source of nonneural SP. The tachykinins interact with each of three cloned neurokinin (NK) receptors (NK-1R, NK-2R, NK-3R) with SP and NK-A exhibiting binding preferences for NK-1R and NK-2R, respectively. Proliferation of myeloid progenitors (CFU-GM) is differentially regulated by SP and NK-A. The former enhances the proliferation whereas the latter is inhibitory. The BM stroma mediates most of the hematopoietic effects exerted by SP and NK-A partly through the induction of cytokines. The proliferative effects of SP correlate with the induction of positive hematopoietic growth factors such as IL-3, IL-6, GM-CSF and c-kit ligand and the inhibitory effects by NK-A correlate with the induction of two negative hematopoietic regulators, MIP-1 alpha and TGF-beta. Intracellular signals mediated by NK-1R and NK-2R are part of the mechanism responsible for tachykinin-mediated regulation of hematopoiesis. The stimulatory effects on BM progenitors mediated by NK-1R can be partly inhibited by NK-2R activation. IL-1 and other cytokines induced by SP in BM stroma modulate NK-1R induction. Furthermore, SP can induce IL-1 type I receptor in stroma. Together, these data suggest that the tachykinins and the cytokines interact to regulate hematopoiesis. These interactions contribute to hematopoietic regulation by mechanisms that involve induction of: (1) tachykinins and cytokines by each other; (2) NK-1R by cytokines and (3) cytokine receptor by the tachykinins. These studies emphasize that in terms of hematopoiesis, the cytokines and neuropeptides are not mutually exclusive factors and thus, the hematopoietic regulatory network would be incomplete without the role of neuropeptides being considered.
我们一直在研究速激肽对造血的影响，速激肽与许多其他神经肽一样，可在神经组织和非神经组织中表达。速激肽家族成员P物质（SP）和神经激肽A（NK-A）是免疫和造血调节剂。SP和NK-A通过可变剪接和翻译后修饰从前速激肽原-I基因（PPT-I）衍生而来。在骨髓（BM）中，神经纤维是神经源性SP的来源，而基质是非神经源性SP的来源。速激肽与三种克隆的神经激肽（NK）受体（NK-1R、NK-2R、NK-3R）相互作用，SP和NK-A分别对NK-1R和NK-2R表现出结合偏好。髓系祖细胞（CFU-GM）的增殖受到SP和NK-A的不同调节。前者促进增殖，而后者具有抑制作用。BM基质部分通过细胞因子的诱导介导SP和NK-A发挥的大多数造血作用。SP的增殖作用与诱导阳性造血生长因子如IL-3、IL-6、GM-CSF和c-kit配体相关，而NK-A的抑制作用与诱导两种阴性造血调节因子MIP-1α和TGF-β相关。由NK-1R和NK-2R介导的细胞内信号是速激肽介导的造血调节机制的一部分。NK-2R激活可部分抑制NK-1R介导的对BM祖细胞的刺激作用。SP在BM基质中诱导的IL-1和其他细胞因子调节NK-1R的诱导。此外，SP可在基质中诱导I型IL-1受体。总之，这些数据表明速激肽和细胞因子相互作用以调节造血。这些相互作用通过涉及以下诱导的机制促进造血调节：（1）速激肽和细胞因子相互诱导；（2）细胞因子诱导NK-1R；（3）速激肽诱导细胞因子受体。这些研究强调，就造血而言，细胞因子和神经肽不是相互排斥的因素，因此，如果不考虑神经肽的作用，造血调节网络将是不完整的。
