Laboratory of Signaling Proteins, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, R. Weigla 12, 53-114 Wrocław, Poland.
Immunobiology. 2011 Mar;216(3):423-30. doi: 10.1016/j.imbio.2010.06.006. Epub 2010 Jul 24.
Inflammation involves the cooperation of various cells and biologically active molecules. An important intracellular messenger molecule participating in the regulation of the process is cyclic GMP (cGMP), which is synthesized by guanylyl cyclases (GCs). The GC family comprises cytosolic (soluble) and membrane-bound (particulate) enzymes. The aim of this study was to determine whether and how the synthesis of cGMP by various forms of GC affects the expression of inflammatory cytokines depending on the activity of the transcription factors NF-κB (nuclear factor-κB) and AP-1 (activator protein-1). We established that in rat peripheral blood mononuclear cells (PBMCs), synthesis of cGMP was elevated by sodium nitroprusside (SNP), the activator of soluble GC, and by atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP), the activators of particulate GC-A and GC-B, respectively. Stimulation of various GCs differently affected the expressions of the cytokines IL-1β, IL-6, and TNF-α in control cells and in cells activated by bacterial endotoxin (LPS). In control PBMCs their expression was elevated by stimulation of soluble, but not particulate, GC. SNP caused an increase in NF-κB activity, but had no influence on the activity of AP-1. The cells treated with LPS decreased the expressions of IL-1β, IL-6, and TNF-α in response to stimulation of particulate GC-A, but not other guanylyl cyclases. This inhibitory effect was a result of suppression of the activities of NF-κB and AP-1. Both effects that of SNP and of ANP, were cGMP dependent, as shown using its membrane-permeable analog 8-Br-cGMP. The implementation of specific inhibitors showed that the stimulatory effect of SNP was mediated by soluble GC and cGMP-dependent protein kinase (PKG-I). However, PKG-I was not involved in the inhibition of NF-κB and AP-1 activities by ANP in LPS-activated cells. Taken together, these results for the first time indicate that various GCs and various cGMP-dependent signaling pathways can modulate the activity of AP-1 and/or NF-κB and thus affect the expressions of IL-1β, IL-6, and TNF-α, which play important roles in the development of inflammation.
炎症涉及各种细胞和生物活性分子的合作。参与调节该过程的一种重要的细胞内信使分子是环鸟苷酸（cGMP），它由鸟苷酸环化酶（GCs）合成。GC 家族包括细胞溶质（可溶性）和膜结合（颗粒状）酶。本研究的目的是确定不同形式的 GC 通过 cGMP 的合成是否以及如何影响炎症细胞因子的表达，这取决于转录因子 NF-κB（核因子-κB）和 AP-1（激活蛋白-1）的活性。我们发现，在大鼠外周血单核细胞（PBMCs）中，可溶性 GC 的激活剂硝普钠（SNP）和颗粒状 GC-A 和 GC-B 的激活剂心钠肽（ANP）和 C 型利钠肽（CNP）分别升高了 cGMP 的合成。各种 GC 的刺激以不同的方式影响了在对照细胞和细菌内毒素（LPS）激活的细胞中细胞因子 IL-1β、IL-6 和 TNF-α的表达。在对照 PBMCs 中，可溶性 GC 的刺激会导致其表达升高，但颗粒状 GC 则不会。SNP 导致 NF-κB 活性增加，但对 AP-1 活性没有影响。用 LPS 处理的细胞在刺激颗粒状 GC-A 时降低了 IL-1β、IL-6 和 TNF-α的表达，但对其他鸟苷酸环化酶则没有。这种抑制作用是 NF-κB 和 AP-1 活性受到抑制的结果。如使用其膜通透性类似物 8-Br-cGMP 所示，SNP 和 ANP 的两种作用均依赖于 cGMP。特定抑制剂的实施表明，SNP 的刺激作用是由可溶性 GC 和 cGMP 依赖性蛋白激酶（PKG-I）介导的。然而，PKG-I 并未参与 LPS 激活细胞中 ANP 对 NF-κB 和 AP-1 活性的抑制。总之，这些结果首次表明，各种 GC 和各种 cGMP 依赖性信号通路可以调节 AP-1 和/或 NF-κB 的活性，从而影响 IL-1β、IL-6 和 TNF-α的表达，这些细胞因子在炎症的发展中起着重要作用。
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