Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Gastroenterology, Kitakyushu Municipal Medical Center, Fukuoka, Japan.
Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan.
PLoS One. 2014 May 5;9(5):e92960. doi: 10.1371/journal.pone.0092960. eCollection 2014.
The etiology of post-inflammatory gastrointestinal (GI) motility dysfunction, after resolution of acute symptoms of inflammatory bowel diseases (IBD) and intestinal infection, is largely unknown, however, a possible involvement of T cells is suggested.
Using the mouse model of T cell activation-induced enteritis, we investigated whether enhancement of smooth muscle cell (SMC) contraction by interleukin (IL)-17A is involved in postinflammatory GI hypermotility.
Activation of CD3 induces temporal enteritis with GI hypomotility in the midst of, and hypermotility after resolution of, intestinal inflammation. Prolonged upregulation of IL-17A was prominent and IL-17A injection directly enhanced GI transit and contractility of intestinal strips. Postinflammatory hypermotility was not observed in IL-17A-deficient mice. Incubation of a muscle strip and SMCs with IL-17A in vitro resulted in enhanced contractility with increased phosphorylation of Ser19 in myosin light chain 2 (p-MLC), a surrogate marker as well as a critical mechanistic factor of SMC contractility. Using primary cultured murine and human intestinal SMCs, IκBζ- and p38 mitogen-activated protein kinase (p38MAPK)-mediated downregulation of the regulator of G protein signaling 4 (RGS4), which suppresses muscarinic signaling of contraction by promoting inactivation/desensitization of Gαq/11 protein, has been suggested to be involved in IL-17A-induced hypercontractility. The opposite effect of L-1β was mediated by IκBζ and c-jun N-terminal kinase (JNK) activation.
We propose and discuss the possible involvement of IL-17A and its downstream signaling cascade in SMCs in diarrheal hypermotility in various GI disorders.
炎症后胃肠道（GI）运动功能障碍的病因，在炎症性肠病（IBD）和肠道感染的急性症状消退后，在很大程度上尚不清楚，但提示 T 细胞可能参与其中。
我们使用 T 细胞激活诱导肠炎的小鼠模型，研究白细胞介素（IL）-17A 是否增强平滑肌细胞（SMC）收缩参与炎症后 GI 高动力性。
CD3 的激活诱导肠内炎症期间和炎症消退后 GI 动力低下的阶段性肠炎，IL-17A 的长期上调尤为突出，IL-17A 注射直接增强 GI 转运和肠段收缩性。在缺乏 IL-17A 的小鼠中未观察到炎症后高动力性。体外将肌肉条带和 SMC 与 IL-17A 孵育导致收缩性增强，肌球蛋白轻链 2（p-MLC）Ser19 磷酸化增加，这是 SMC 收缩性的替代标志物和关键机制因素。使用原代培养的鼠和人肠 SMC，已提出 IκBζ 和 p38 丝裂原活化蛋白激酶（p38MAPK）介导的 G 蛋白信号转导调节因子 4（RGS4）下调参与 IL-17A 诱导的高收缩性，其通过促进 Gαq/11 蛋白失活/脱敏来抑制收缩的毒蕈碱信号。L-1β 的相反作用是通过 IκBζ 和 c-jun N 末端激酶（JNK）激活介导的。
我们提出并讨论了 IL-17A 及其下游信号级联在各种 GI 疾病中 SMC 中可能参与腹泻性高动力性。
