Helicobacter pylori CagA triggers expression of the bactericidal lectin REG3γ via gastric STAT3 activation.
Helicobacter pylori CagA triggers expression of the bactericidal lectin REG3γ via gastric STAT3 activation.
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DOI：
10.1371/journal.pone.0030786
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Menheniott TR
中科院分区：
文献类型：
--
作者：
Lee KS;Kalantzis A;Jackson CB;O'Connor L;Murata-Kamiya N;Hatakeyama M;Judd LM;Giraud AS;Menheniott TR
大多数关于幽门螺杆菌（H。pylori）细胞毒素，CagA，属于作为胃炎症和癌症的决定因素的备受吹嘘的作用。很少有人关注CagA在大多数H. pylori感染个体未显示致癌进展，特别是与宿主耐受性相关。再生胰岛衍生（REG）3γ编码分泌的C型凝集素，其对肠道中的革兰氏阳性菌发挥直接杀菌活性。在这里，我们扩展了凝集素介导的先天免疫的范例，表明REG 3 γ表达是由H.幽门感染的胃在人胃粘膜组织中，与CagA阴性的H. pylori感染者。使用转染的CagA诱导的胃MKN 28细胞，我们在体外重现了REG 3 γ诱导，也表明酪氨酸磷酸化的而不是未磷酸化的CagA触发REG 3 γ转录。与诱导的REG 3 γ一致，gp 130细胞因子共受体下游通过信号转导和转录激活因子（STAT）3的促炎信号传导以及两种同源配体白细胞介素（IL）-11和IL-6的转录显著增加。外源性IL-11而非IL-6直接刺激STAT 3活化和REG 3 γ转录。STAT 3 siRNA敲除或IL-11受体阻断分别消除或减弱CagA依赖性REG 3 γ mRNA诱导，从而证明需要通过IL-11/STAT 3途径进行未受损的信号传导。抑制gp 130相关的SHP 2-（Ras）-ERK通路不影响CagA依赖的REG 3 γ诱导，但增强了STAT 3激活以及增强了粘膜先天免疫调节因子IL-6、IL-8和干扰素应答因子（IRF）1的转录。我们的结果支持胃上皮细胞中CagA介导的REG 3 γ表达通过激活IL-11/gp 130/STAT 3途径的模型。这种反应可能会使革兰氏阴性H。幽门螺杆菌操纵宿主免疫，有利于自己的生存，通过减少共生革兰氏阳性菌的健身，它竞争的胃粘膜生态位的资源。
Most of what is known about the Helicobacter pylori (H. pylori) cytotoxin, CagA, pertains to a much-vaunted role as a determinant of gastric inflammation and cancer. Little attention has been devoted to potential roles of CagA in the majority of H. pylori infected individuals not showing oncogenic progression, particularly in relation to host tolerance. Regenerating islet-derived (REG)3γ encodes a secreted C-type lectin that exerts direct bactericidal activity against Gram-positive bacteria in the intestine. Here, we extend this paradigm of lectin-mediated innate immunity, showing that REG3γ expression is triggered by CagA in the H. pylori-infected stomach. In human gastric mucosal tissues, REG3γ expression was significantly increased in CagA-positive, compared to CagA-negative H. pylori infected individuals. Using transfected CagA-inducible gastric MKN28 cells, we recapitulated REG3γ induction in vitro, also showing that tyrosine phosphorylated, not unphosphorylated CagA triggers REG3γ transcription. In concert with induced REG3γ, pro-inflammatory signalling downstream of the gp130 cytokine co-receptor via the signal transducer and activator of transcription (STAT)3 and transcription of two cognate ligands, interleukin(IL)-11 and IL-6, were significantly increased. Exogenous IL-11, but not IL-6, directly stimulated STAT3 activation and REG3γ transcription. STAT3 siRNA knockdown or IL-11 receptor blockade respectively abrogated or subdued CagA-dependent REG3γ mRNA induction, thus demonstrating a requirement for uncompromised signalling via the IL-11/STAT3 pathway. Inhibition of the gp130-related SHP2-(Ras)-ERK pathway did not affect CagA-dependent REG3γ induction, but strengthened STAT3 activation as well as augmenting transcription of mucosal innate immune regulators, IL-6, IL-8 and interferon-response factor (IRF)1. Our results support a model of CagA-directed REG3γ expression in gastric epithelial cells via activation of the IL-11/gp130/STAT3 pathway. This response might allow Gram-negative H. pylori to manipulate host immunity to favour its own survival, by reducing the fitness of co-habiting Gram-positive bacteria with which it competes for resources in the gastric mucosal niche.
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DOI：
10.1086/590158
发表时间：
2008-08-15
期刊：
The Journal of infectious diseases
影响因子：
--
作者：
Chen Y;Blaser MJ
通讯作者：
Blaser MJ
影响因子：
4.8
作者：
Gharavi, Nima M.;Alva, Jackelyn A.;Berliner, Judith A.
通讯作者：
Berliner, Judith A.
影响因子：
4.8
作者：
Higashi, H;Yokoyama, K;Hatakeyama, M
通讯作者：
Hatakeyama, M
影响因子：
3.4
作者：
CRABTREE, JE;COVACCI, A;RAPPUOLI, R
通讯作者：
RAPPUOLI, R
影响因子：
29.4
作者：
Howlett, M;Judd, LM;Giraud, AS
通讯作者：
Giraud, AS