Innate PI3K p110δ regulates Th1/Th17 development and microbiota-dependent colitis.
Innate PI3K p110δ regulates Th1/Th17 development and microbiota-dependent colitis.
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DOI：
10.4049/jimmunol.1301533
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发表时间：
2014-04-15
期刊：
影响因子：
--
通讯作者：
Plevy SE
中科院分区：
文献类型：
--
作者：
Steinbach EC;Kobayashi T;Russo SM;Sheikh SZ;Gipson GR;Kennedy ST;Uno JK;Mishima Y;Borst LB;Liu B;Herfarth H;Ting JP;Sartor RB;Plevy SE
IA类磷酸肌醇3-激酶的p110δ亚基调节先天免疫细胞中的信号传导。我们以前证明，小鼠携带激酶死亡p110δ亚基（p110δKD）发展自发性结肠炎。巨噬细胞通过增加IL-12和IL-23的表达而促进了p110δKD小鼠中Th 1/Th 17细胞因子的偏倚。在这里，我们表明肠道微生物群是无菌p110δKD小鼠结肠炎发展所必需的。与野生型（WT）小鼠相比，p110δKD小鼠的结肠组织和巨噬细胞产生的IL-10显著减少。与WT APC相比，与初始CD 4+抗原特异性T细胞共培养的p110δKD APC也产生显著更少的IL-10，并诱导更多的产生IFN-γ和IL-17 A的CD 4 + T细胞。说明APC - T细胞相互作用在体内结肠炎发病机制中的重要性，Rag 1-/-/p110δKD小鼠发生轻度结肠炎症，并且与Rag 1-/-小鼠相比产生更多的结肠IL-12 p40。然而，与Rag 1-/-受体小鼠相比，CD 4 + CD 45 RB高/低T细胞Rag 1-/-/p110δKD受体小鼠发生重度结肠炎，产生IFN-γ和IL-17 A的固有层CD 3 + CD 4 + T细胞的百分比增加。与来自非IBD对照受试者的肠样品相比，来自克罗恩病患者的肠组织样品显示出显著较低的PIK 3CD表达（p<0.05）。PIK 3 CD表达与IL 12 B：IL 10表达的比率呈负相关。总之，PI 3 K亚基p110δ通过改变IL-10和IL-12/23之间的平衡来控制稳态APC - T细胞相互作用。p110δ表达和/或功能的缺陷可能是人类IBD发病机制的基础，并导致新的治疗策略。
The p110δ subunit of class IA phosphoinositide 3-kinase modulates signaling in innate immune cells. We previously demonstrated that mice harboring a kinase-dead p110δ subunit (p110δKD) develop spontaneous colitis. Macrophages contributed to the Th1/Th17 cytokine bias in p110δKD mice through increased IL-12 and IL-23 expression. Here, we show that the enteric microbiota is required for colitis development in germ free p110δKD mice. Colonic tissue and macrophages from p110δKD mice produce significantly less IL-10 compared to wild type (WT) mice. p110δKD APC co-cultured with naïve CD4+ antigen-specific T cells also produce significantly less IL-10, and induce more IFN-γ- and IL-17A-producing CD4+ T cells compared to WT APC. Illustrating the importance of APC – T cell interactions in colitis pathogenesis in vivo, Rag1-/-/p110δKD mice develop mild colonic inflammation and produced more colonic IL-12p40 compared to Rag1-/- mice. However, CD4+CD45RBhigh/low T cell Rag1-/-/p110δKD recipient mice develop severe colitis with increased percentages of IFN-γ- and IL-17A-producing lamina propria CD3+CD4+ T cells compared to Rag1-/- recipient mice. Intestinal tissue samples from patients with Crohn’s disease reveal significantly lower expression of PIK3CD compared to intestinal samples from non-IBD control subjects (p<0.05). PIK3CD expression inversely correlated with the ratio of IL12B:IL10 expression. In conclusion, the PI3K subunit p110δ controls homeostatic APC – T cell interactions by altering the balance between IL-10 and IL-12/23. Defects in p110δ expression and/or function may underlie the pathogenesis of human IBD and lead to new therapeutic strategies.
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影响因子：
64.5
作者：
Ivanov, Ivaylo I.;McKenzie, Brent S.;Littman, Dan R.
通讯作者：
Littman, Dan R.
磷酸肌醇3-激酶δ调节高尔基体载体的膜裂变，以进行选择性细胞因子分泌。
DOI：
10.1083/jcb.201001028
发表时间：
2010-09-20
期刊：
The Journal of cell biology
影响因子：
--
作者：
Low PC;Misaki R;Schroder K;Stanley AC;Sweet MJ;Teasdale RD;Vanhaesebroeck B;Meunier FA;Taguchi T;Stow JL
通讯作者：
Stow JL
影响因子：
30.5
作者：
Fukao, T;Tanabe, M;Koyasu, S
通讯作者：
Koyasu, S
影响因子：
6.4
作者：
Antoniv, Taras T.;Ivashkiv, Lionel B.
通讯作者：
Ivashkiv, Lionel B.
影响因子：
16.8
作者：
Fukao, T;Koyasu, S
通讯作者：
Koyasu, S