The antimicrobial peptide cathelicidin modulates Clostridium difficile-associated colitis and toxin A-mediated enteritis in mice.
The antimicrobial peptide cathelicidin modulates Clostridium difficile-associated colitis and toxin A-mediated enteritis in mice.
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DOI：
10.1136/gutjnl-2012-302180
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发表时间：
2013-09
期刊：
影响因子：
24.5
通讯作者：
Koon HW
中科院分区：
文献类型：
--
作者：
Hing TC;Ho S;Shih DQ;Ichikawa R;Cheng M;Chen J;Chen X;Law I;Najarian R;Kelly CP;Gallo RL;Targan SR;Pothoulakis C;Koon HW
艰难梭菌通过释放毒素 A (TxA)（一种强效肠毒素）来介导肠道炎症。 Cathelicidins（Camp 基因名称，人类中的 LL-37 肽和小鼠中的 mCRAMP 肽）是抗菌肽，也具有抗炎特性。确定导管素在艰难梭菌感染和 TxA 介导的回肠炎症模型以及培养的人原代单核细胞中的作用。野生型（WT）和mCRAMP缺陷（Camp−/−）小鼠用抗生素混合物治疗并口服艰难梭菌感染。一些小鼠每天结肠内注射 mCRAMP，持续 3 天。还在 WT 小鼠中制备回肠环，并用盐水或 TxA 处理并孵育 4 小时，同时向一些 TxA 处理的环注射 mCRAMP。对艰难梭菌感染的 WT 小鼠进行结肠内 mCRAMP 给药后，结肠组织学损伤、细胞凋亡、组织髓过氧化物酶 (MPO) 和肿瘤坏死因子 (TNF)α 水平显着降低。回肠 mCRAMP 治疗还显着降低了暴露于 TxA 的回肠环中的组织学损伤、组织细胞凋亡、MPO 和 TNFα 水平。 WT 和 Camp−/− 小鼠在两种模型中表现出相似的肠道反应，这意味着艰难梭菌/TxA 诱导的内源性抗菌肽可能不足以调节艰难梭菌/TxA 介导的肠道炎症。 LL-37 和 mCRAMP 还通过抑制 NF-κB 磷酸化显着减少 TxA 诱导的 TNFα 分泌。内源性导管素不能控制艰难梭菌和/或毒素 A 介导的炎症，甚至人类和小鼠的肠道导管素表达增加。外源性导管素通过抑制 TxA 相关肠道炎症来调节艰难梭菌结肠炎。给予导管素可能是治疗艰难梭菌毒素相关疾病的一种新的抗炎治疗方法。
Clostridium difficile mediates intestinal inflammation by releasing toxin A (TxA), a potent enterotoxin. Cathelicidins (Camp as gene name, LL-37 peptide in humans and mCRAMP peptide in mice) are antibacterial peptides that also posses anti-inflammatory properties. To determine the role of cathelicidins in models of Clostridium difficile infection and TxA-mediated ileal inflammation and cultured human primary monocytes. Wild-type (WT) and mCRAMP-deficient (Camp−/−) mice were treated with an antibiotic mixture and infected orally with C difficile. Some mice were intracolonically given mCRAMP daily for 3 days. Ileal loops were also prepared in WT mice and treated with either saline or TxA and incubated for 4 h, while some TxA-treated loops were injected with mCRAMP. Intracolonic mCRAMP administration to C difficile-infected WT mice showed significantly reduced colonic histology damage, apoptosis, tissue myeloperoxidase (MPO) and tumour necrosis factor (TNF)α levels. Ileal mCRAMP treatment also significantly reduced histology damage, tissue apoptosis, MPO and TNFα levels in TxA-exposed ileal loops. WT and Camp−/− mice exhibited similar intestinal responses in both models, implying that C difficile/TxA-induced endogenous cathelicidin may be insufficient to modulate C difficile/TxA-mediated intestinal inflammation. Both LL-37 and mCRAMP also significantly reduced TxA-induced TNFα secretion via inhibition of NF-κB phosphorylation. Endogenous cathelicidin failed to control C difficile and/or toxin A-mediated inflammation and even intestinal cathelicidin expression was increased in humans and mice. Exogenous cathelicidin modulates C difficile colitis by inhibiting TxA-associated intestinal inflammation. Cathelicidin administration may be a new anti-inflammatory treatment for C difficile toxin-associated disease.
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DOI：
10.1056/nejmra0707500
发表时间：
2008-10-30
期刊：
The New England journal of medicine
影响因子：
--
作者：
Kelly, Ciaran P;LaMont, J Thomas
通讯作者：
LaMont, J Thomas
影响因子：
29.4
作者：
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通讯作者：
Aktories, Klaus
DOI：
10.1111/j.1440-1746.2009.06135.x
发表时间：
2010-04-01
影响因子：
4.1
作者：
Kaur, Sukhminderjit;Vaishnavi, Chetana;Prasad, Kaushal Kishor
通讯作者：
Prasad, Kaushal Kishor
影响因子：
29.4
作者：
Chen, Xinhua;Katchar, Kianoosh;Kelly, Ciaran P.
通讯作者：
Kelly, Ciaran P.
影响因子：
4.8
作者：
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Gennaro, R