Department of Pulmonary Immunology, University of Texas Health Science Center, Tyler.
Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires, Universidad Nacional del Noroeste de la Provincia de Buenos Aires- Consejo Nacional de Investigaciones Científicas y Técnicas, Junín, Argentina.
J Infect Dis. 2018 May 5;217(11):1821-1831. doi: 10.1093/infdis/jiy079.
Cyclic adenosine monophosphate (cAMP) is critical in immune regulation, and its role in tuberculosis infection remains unclear. We determined the levels of cAMP in peripheral blood mononuclear cells (PBMC) from tuberculosis patients and the mechanisms for cAMP suppression of IFN-γ production. PBMC from tuberculosis patients contained significantly elevated cAMP than latent tuberculosis infected subjects (LTBI), with an inverse correlation with IFN-γ production. Consistent with this, the expression of cAMP response element binding protein (CREB), activating transcription factor (ATF)-2 and c-Jun were reduced in tuberculosis patients compared with LTBI. PKA type I specific cAMP analogs inhibited Mtb-stimulated IFN-g production by PBMC through suppression of Mtb-induced IFN-γ promoter binding activities of CREB, ATF-2, and c-Jun and also miR155, the target miRNA of these transcription factors. Neutralizing both IL-10 and TGF-β1 or supplementation of IL-12 restored cAMP-suppressed IFN-g production. We conclude that increased cAMP inhibits IFN-g production through PKA type I pathway in tuberculosis infection.
环磷酸腺苷 (cAMP) 在免疫调节中至关重要，但其在结核病感染中的作用尚不清楚。我们测定了结核病患者外周血单个核细胞（PBMC）中的 cAMP 水平，以及 cAMP 抑制 IFN-γ 产生的机制。与潜伏性结核感染（LTBI）相比，结核病患者的 PBMC 中 cAMP 含量明显升高，与 IFN-γ 产生呈负相关。与此一致的是，与 LTBI 相比，结核病患者的 cAMP 反应元件结合蛋白（CREB）、激活转录因子（ATF）-2 和 c-Jun 的表达减少。PKA 型 I 特异性 cAMP 类似物通过抑制 Mtb 诱导的 CREB、ATF-2 和 c-Jun 以及这些转录因子的靶 miRNA miR155 对 IFN-γ 启动子的结合活性，抑制 Mtb 刺激的 PBMC 中 IFN-γ 的产生。中和 IL-10 和 TGF-β1 或补充 IL-12 恢复了 cAMP 抑制的 IFN-γ 产生。我们得出结论，在结核病感染中，增加的 cAMP 通过 PKA 型 I 途径抑制 IFN-γ 的产生。
