Occupational Therapy Division, Faculty of Physical Therapy, Mahidol University, Nakornpathom 73170, Thailand.
Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota, Grand Forks, ND 58202, USA.
Life Sci. 2016 Jan 1;144:19-25. doi: 10.1016/j.lfs.2015.11.015. Epub 2015 Nov 18.
Calcitonin gene-related peptides (CGRP), an endogenous neuropeptide, play an important role in the development of neuroinflammation by acting upon its receptor. The CGRP receptor immunoreactivity was identified on Schwann cells. However the effects of CGRP on Schwann cells are unknown and the exact signaling mechanisms associated with CGRP receptor activation related to Schwann cells inflammatory responses are not well understood. We investigated the effect of CGRP on CGRP receptor activation mediates a proinflammatory signaling response in Schwann cells.
CGRP-induced ERK-MAPK phosphorylation and proinflammatory cytokines, interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor (TNF-α) expressions were measured by immune blotting. We also used specific antagonist and inhibitors to confirm the exactly signaling pathway including CGRP (8-37), SQ 22536 and H-89.
Treatment with CGRP demonstrated a significant generation of IL-1β and IL-6 but not in the level of TNF-α. In addition, there was a temporal increase in the activated form of ERK caused by CGRP that was prevented after pretreatment with CGRP (8-37), SQ 22536 and H-89. Furthermore, use of the CGRP (8-37), ERK inhibitor PD 98059, SQ 22536 or H-89 abolished the CGRP mediated increase in IL-1β.
This investigation provides evidence for a novel CGRP activation on Schwann cells that mediates inflammatory response by increasing of IL-1β and IL-6 expression. CGRP activates the cAMP-PKA-ERK signaling cascade leading to IL-1β production. These results support the notion that CGRP may play a direct role to initiate inflammatory processes in the peripheral nervous system.
降钙素基因相关肽（CGRP）是一种内源性神经肽，通过作用于其受体在神经炎症的发展中发挥重要作用。CGRP 受体免疫反应性在施万细胞上被鉴定。然而，CGRP 对施万细胞的影响尚不清楚，与 CGRP 受体激活相关的施万细胞炎症反应的确切信号机制也尚未完全理解。我们研究了 CGRP 对 CGRP 受体激活的影响，该激活介导施万细胞的促炎信号反应。
通过免疫印迹法测量 CGRP 诱导的 ERK-MAPK 磷酸化和促炎细胞因子白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）和肿瘤坏死因子（TNF-α）的表达。我们还使用了特异性拮抗剂和抑制剂来证实包括 CGRP（8-37）、SQ 22536 和 H-89 在内的确切信号通路。
CGRP 的处理显示出显著的 IL-1β 和 IL-6 生成，但 TNF-α 水平没有增加。此外，CGRP 引起 ERK 激活形式的时间依赖性增加，在用 CGRP（8-37）、SQ 22536 和 H-89 预处理后被阻止。此外，使用 CGRP（8-37）、ERK 抑制剂 PD 98059、SQ 22536 或 H-89 消除了 CGRP 介导的 IL-1β 增加。
这项研究提供了证据表明，CGRP 可激活施万细胞，通过增加 IL-1β 和 IL-6 的表达来介导炎症反应。CGRP 激活 cAMP-PKA-ERK 信号级联反应，导致 IL-1β 的产生。这些结果支持了 CGRP 可能在外周神经系统中直接引发炎症过程的观点。
