Zymosan activates protein kinase A via adenylyl cyclase VII to modulate innate immune responses during inflammation.
Zymosan activates protein kinase A via adenylyl cyclase VII to modulate innate immune responses during inflammation.
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DOI：
10.1016/j.molimm.2012.10.027
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发表时间：
2013-05
影响因子：
3.6
通讯作者：
Wang JE
中科院分区：
文献类型：
--
作者：
Jiang LI;Sternweis PC;Wang JE
病原体使用多种策略来逃避宿主的免疫防御。抑制免疫功能的一种有效方法是增加宿主免疫细胞中cAMP的细胞内浓度，从而抑制炎症反应并防止微生物杀伤。我们发现酵母细胞壁提取物酵母聚糖能够增加小鼠骨髓源性巨噬细胞（BMDM）细胞内cAMP并激活蛋白激酶A通路。这种反应依赖于腺苷酸环化酶VII型（AC 7）和异源三聚体G蛋白，主要是G12/13。因此，与野生型细胞中的反应相比，酵母聚糖诱导的炎性细胞因子TNFα在AC 7缺陷小鼠的BMDM中的产生要强得多。在酵母多糖诱导的腹膜炎模型中，骨髓谱系中AC 7缺陷的小鼠显示出长期炎症。我们认为酵母多糖诱导的cAMP增加和PKA活化是抑制宿主细胞炎症反应的一种机制，因此有利于微生物的存活。这也将有助于解释一个有据可查的现象，即酵母聚糖通过TLR 2刺激炎性细胞因子反应的能力似乎比TLR 2的其他刺激物弱。
Pathogens use a variety of strategies to evade host immune defenses. A powerful way to suppress immune function is to increase intracellular concentrations of cAMP in host immune cells, which dampens inflammatory responses and prevents microbial killing. We found that the yeast cell wall extract, zymosan, is capable of increasing intracellular cAMP and activates the protein kinase A pathway in bone marrow derived macrophage (BMDM) cells from mice. This response is dependent on adenylyl cyclase type VII (AC7) and heterotrimeric G proteins, primarily G12/13. Consequently, zymosan induced production of the inflammatory cytokine, TNFα, was much stronger in BMDMs from AC7 deficient mice compared to the response in wild type cells. In a model of zymosan induced peritonitis, mice deficient of AC7 in the myeloid lineage displayed prolonged inflammation. We propose that zymosan induced increases in cAMP and activation of PKA serve as a mechanism to dampen inflammatory responses in host cells, which consequently favors the survival of microbes. This would also help explain a well documented phenomenon, that the ability of zymosan to stimulate inflammatory cytokine responses via TLR2 appears to be weaker than other stimuli of TLR2.
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