Buckley T L, Brain S D, Collins P D, Williams T J
Department of Applied Pharmacology, National Heart and Lung Institute, London, United Kingdom.
J Immunol. 1991 May 15;146(10):3424-30.
The neuropeptide calcitonin gene-related peptide (CGRP) is a potent vasodilator with a long duration of action. CGRP is widely distributed and is present in perivascular nerves of tissues that include skin and the synovium. In this study we have investigated the possibility that CGRP can modulate the inflammatory actions of the cytokine IL-1 by using an inflammatory model in rabbit skin. The intradermal injection of IL-1 (1.4 x 10(-14) mol/site) alone stimulated little edema formation. However, when IL-1 was injected with CGRP (10(-11) mol/site), a highly significant edema was observed, and neutrophil accumulation induced by IL-1 was potentiated. These results suggest that the action of IL-1 as a potent mediator of increased microvascular permeability is only observed when skin blood flow is increased in this model. This was confirmed by experiments in which PGE2 (3 x 10(-9) mol/site) at a dose with a similar duration of vasodilator action as CGRP (10(-11) mol/site) also potentiated edema induced by IL-1. Further experiments investigated the mechanism by which IL-1 increased microvascular permeability. Edema induced by IL-1 was dependent on de novo protein synthesis and the presence of circulating neutrophils. However, selective platelet-activating factor and histamine H1 antagonists had no inhibitory effect on this response. Thus it appears that when a microvascular bed is dilated by the long-lasting vasodilator CGRP, edema induced by IL-1 is clearly observed. These results highlight a potentially important synergistic interaction between cytokines and neuropeptides in inflammation.
神经肽降钙素基因相关肽（CGRP）是一种作用持久的强效血管舒张剂。CGRP分布广泛，存在于包括皮肤和滑膜在内的组织的血管周围神经中。在本研究中，我们利用兔皮肤炎症模型研究了CGRP调节细胞因子IL-1炎症作用的可能性。单独皮内注射IL-1（1.4×10⁻¹⁴摩尔/部位）几乎不刺激水肿形成。然而，当IL-1与CGRP（10⁻¹¹摩尔/部位）一起注射时，观察到高度显著的水肿，并且IL-1诱导的中性粒细胞聚集增强。这些结果表明，在该模型中，只有当皮肤血流增加时，才会观察到IL-1作为微血管通透性增加的强效介质的作用。这通过实验得到证实，实验中剂量与CGRP（10⁻¹¹摩尔/部位）血管舒张作用持续时间相似的PGE2（3×10⁻⁹摩尔/部位）也增强了IL-1诱导的水肿。进一步的实验研究了IL-1增加微血管通透性的机制。IL-1诱导的水肿依赖于从头合成蛋白质和循环中性粒细胞的存在。然而，选择性血小板活化因子和组胺H1拮抗剂对该反应没有抑制作用。因此，当微血管床被长效血管舒张剂CGRP扩张时，明显观察到IL-1诱导的水肿。这些结果突出了细胞因子和神经肽在炎症中潜在的重要协同相互作用。
