Functional antagonism of IL-1α induced gene expression profiles define the cAMP/PKA pathway as a unique regulator of IL-1α signaling networks

Abstract

Interleukin-1 (IL-1α) induced inflammatory and pro-fibrotic responses in human lung fibroblasts are mediated by activation of MAPK and NFκB 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-1α mediated gene changes. A reference set of genes was derived from microarray analysis of IL-1α 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 Gs-coupled receptor agonists have a unique pattern of activity as represented by their impact on IL-1α 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-1α responses by multiple Gs-coupled receptors and regulates IL-1α 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.