Adenosine 5'-monophosphate-activated protein kinase regulates IL-10-mediated anti-inflammatory signaling pathways in macrophages.
Adenosine 5'-monophosphate-activated protein kinase regulates IL-10-mediated anti-inflammatory signaling pathways in macrophages.
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DOI：
10.4049/jimmunol.1401024
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发表时间：
2015-01-15
期刊：
影响因子：
--
通讯作者：
Suttles J
中科院分区：
文献类型：
--
作者：
Zhu YP;Brown JR;Sag D;Zhang L;Suttles J
amp活化蛋白激酶（AMPK）是一种保守的丝氨酸/苏氨酸激酶，在真核细胞的代谢途径调节中起关键作用。最近，AMPK已被证明在白细胞炎症活动的调节中起着额外的作用。用化学AMPK激活剂治疗巨噬细胞，或强迫表达一种组成活性形式的AMPK，导致极化到抗炎表型。此外，我们之前报道了用IL-10、IL-4和TGF-β等抗炎细胞因子刺激巨噬细胞可导致AMPK的快速激活，这表明AMPK参与了这些细胞因子的抑制功能。在本研究中，我们研究了AMPK在il -10诱导的基因表达和抗炎功能中的作用。il -10刺激的野生型巨噬细胞表现出PI3K及其下游靶点Akt和mTORC1的快速激活，而在ampk α1缺陷小鼠产生的巨噬细胞中没有观察到这种作用。AMPK的激活不受PI3K抑制剂LY294002或JAK抑制剂CP-690550的影响，这表明il -10介导的AMPK激活不依赖于PI3K和JAK活性。IL-10诱导STAT3的Tyr705和Ser727残基磷酸化，以AMPKα1依赖的方式，这些磷酸化事件分别被AMPK上游激活因子CaMKKβ和mTORC1抑制剂雷帕霉素抑制。在ampkα 1缺失的巨噬细胞中，STAT3磷酸化对IL-10的反应受损，同时伴有SOCS3表达减少和IL-10不足以抑制lps诱导的促炎细胞因子的产生。总之，我们的数据表明AMPKα1是IL-10激活PI3K/Akt/mTORC1和stat3介导的调节巨噬细胞功能极化的抗炎途径所必需的。
AMP-activated protein kinase, AMPK, is a conserved serine/threonine kinase with a critical function in the regulation of metabolic pathways in eukaryotic cells. Recently, AMPK has been shown to play an additional role as a regulator of inflammatory activity in leukocytes. Treatment of macrophages with chemical AMPK activators, or forced expression of a constitutively active form of AMPK, results in polarization to an antiinflammatory phenotype. Additionally, we reported previously that stimulation of macrophages with antiinflammatory cytokines such as IL-10, IL-4 and TGF-β results in rapid activation of AMPK, suggesting that AMPK contributes to the suppressive function of these cytokines. In the current study we investigated the role of AMPK in IL-10-induced gene expression and antiinflammatory function. IL-10-stimulated wild-type macrophages displayed rapid activation of PI3K and its downstream targets Akt and mTORC1, an effect that was not seen in macrophages generated from AMPKα1-deficient mice. AMPK activation was not impacted by treatment with either the PI3K inhibitor LY294002 or the JAK inhibitor CP-690550, suggesting that IL-10-mediated activation of AMPK is independent of PI3K and JAK activity. IL-10 induced phosphorylation of both Tyr705 and Ser727 residues of STAT3 in an AMPKα1-dependent manner, and these phosphorylation events were blocked by inhibition of CaMKKβ, an upstream activator of AMPK, and by the mTORC1 inhibitor rapamycin, respectively. The impaired STAT3 phosphorylation in response to IL-10 observed in AMPKα1-deficient macrophages was accompanied by reduced SOCS3 expression and an inadequacy of IL-10 to suppress LPS-induced proinflammatory cytokine production. Overall, our data demonstrate that AMPKα1 is required for IL-10 activation of the PI3K/Akt/mTORC1 and STAT3-mediated antiinflammatory pathways regulating macrophage functional polarization.
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DOI：
10.4049/jimmunol.1102975
发表时间：
2013-04-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Guo L;Stripay JL;Zhang X;Collage RD;Hulver M;Carchman EH;Howell GM;Zuckerbraun BS;Lee JS;Rosengart MR
通讯作者：
Rosengart MR
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：
4.8
作者：
Inukai, K;Anai, M;Asano, T
通讯作者：
Asano, T
影响因子：
4.8
作者：
Crawley, JB;Williams, LM;Foxwell, BMJ
通讯作者：
Foxwell, BMJ
影响因子：
64.5
作者：
Jacinto, Estela;Facchinetti, Valeria;Su, Bing
通讯作者：
Su, Bing