Murray David L, Johnson Eric N, Wang Ping, Gauthier Josee, Bing Nan, Vanderwall Dana, Xu Zangwei, Jensen David, Cox Richard F, Kostura Matthew, Sorensen Scott D
Discovery Research and Chemoinformatics, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
J Recept Signal Transduct Res. 2009;29(5):246-56. doi: 10.1080/10799890903078473.
Interleukin-1 (IL-1alpha) induced inflammatory and pro-fibrotic responses in human lung fibroblasts are mediated by activation of MAPK and NFkappaB pathways. The purpose of the present study was to broadly profile the activity of a variety of compounds which function as inhibitors of these key signaling pathways that may affect IL-1alpha mediated gene changes. A reference set of genes was derived from microarray analysis of IL-1alpha stimulated cells. The genes were chosen to provide a range of expression profiles which serve to represent the actions of the underlying signaling network. We show that G(s)-coupled receptor agonists have a unique pattern of activity as represented by their impact on IL-1alpha dependent gene changes. These effects were not mimicked by direct inhibitors of p38, JNK, MEK or IKK but were mimicked by forskolin and cAMP analogs. These findings indicate that cAMP/PKA serves as a point of convergence for regulation of IL-1alpha responses by multiple G(s)-coupled receptors and regulates IL-1alpha responses by a distinct mechanism that does not solely involve direct inhibition of p38, JNK, MEK or IKK. The data also point to a potentially useful paradigm wherein monitoring of a small subset of genes is sufficient to identify pathway activity of novel compounds.
白细胞介素-1（IL-1α）在人肺成纤维细胞中诱导的炎症和促纤维化反应是由丝裂原活化蛋白激酶（MAPK）和核因子κB（NFκB）信号通路的激活介导的。本研究的目的是广泛分析多种化合物的活性，这些化合物作为这些关键信号通路的抑制剂，可能影响IL-1α介导的基因变化。一组参考基因来自对IL-1α刺激细胞的微阵列分析。选择这些基因是为了提供一系列表达谱，以代表潜在信号网络的作用。我们发现，G(s)偶联受体激动剂具有独特的活性模式，其对IL-1α依赖性基因变化的影响就是例证。这些效应不能被p38、JNK、MEK或IKK的直接抑制剂模拟，但能被福斯可林和环磷酸腺苷（cAMP）类似物模拟。这些发现表明，cAMP/蛋白激酶A（PKA）作为多个G(s)偶联受体调节IL-1α反应的汇聚点，并通过一种不单纯涉及直接抑制p38、JNK、MEK或IKK的独特机制调节IL-1α反应。数据还指向一个潜在有用的范例，即监测一小部分基因就足以识别新型化合物的信号通路活性。
