Analysis of caspase-1 regulated transcriptome in various tissues lead to identification of novel IL-1β, IL-18 and sirtuin-1 intendent pathways

Abstract

Abstract Caspase-1 is prominently involved in bridging disease risk factors/ danger signals to inflammatory response via its downstream targets such as IL (interleukin)-1β, IL-18, and Sirt-1 (Sirtuin-1). The microarray datasets derived from caspase-1 knockout tissues indicated that caspase-1 function can significantly impact the transcriptome. However, it is not known whether all effects exerted by caspase-1 on transcriptome are mediated only by its well-known substrates. Therefore, we hypothesized that the effects of caspase-1 on transcriptome may be partially independent from IL-1β, IL-18, and Sirt-1. To determine new global and tissue-specific gene regulatory effects of caspase-1, we took novel microarray data analysis approaches including Venn analysis, cooperation analysis, and meta-analysis. We made the following important findings: (1) Caspase-1 exerts its regulatory effects on majority of genes in a tissue-specific manner; (2) Caspase-1 regulatory genes partially cooperates with genes regulated by Sirt-1 during organ injury and inflammation in adipose tissue but not in liver; (3) Caspase-1 cooperates with IL-1β in regulating less than half of the genes involved in organismal injury, and cancer in mouse liver; (4) The meta-analysis identified 40 caspase-1 globally regulated genes across tissues, suggesting that caspase-1 globally regulates many novel pathways; and (5) The meta-analysis identified new cooperatively and non-cooperatively regulated genes in caspase-1, IL-1β, IL-18, and Sirt-1 pathways. Our findings suggest that caspase-1 regulates many new signaling pathways potentially via its known substrates and also via transcription factors and other proteins that are yet to be identified.