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Analyses of caspase-1-regulated transcriptomes in various tissues lead to identification of novel IL-1?-, IL-18- and sirtuin-1-independent pathways.

ABSTRACT: BACKGROUND:It is well established that caspase-1 exerts its biological activities through its downstream targets such as IL-1?, IL-18, and Sirt-1. The microarray datasets derived from various caspase-1 knockout tissues indicated that caspase-1 can significantly impact the transcriptome. However, it is not known whether all the 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-1?, IL-18, and Sirt-1. METHODS: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 methods. We used these statistical methods to integrate different microarray datasets conducted on different caspase-1 knockout tissues and datasets where caspase-1 downstream targets were manipulated. RESULTS:We made the following important findings: (1) Caspase-1 exerts its regulatory effects on the majority of genes in a tissue-specific manner; (2) Caspase-1 regulatory genes partially cooperates with genes regulated by sirtuin-1 during organ injury and inflammation in adipose tissue but not in the liver; (3) Caspase-1 cooperates with IL-1? in regulating less than half of the genes involved in cardiovascular disease, organismal injury, and cancer in mouse liver; (4) The meta-analysis identifies 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-1?, IL-18, and Sirt-1 pathways. CONCLUSIONS: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.

SUBMITTER: Li YF

PROVIDER: S-EPMC5290602 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Analyses of caspase-1-regulated transcriptomes in various tissues lead to identification of novel IL-1β-, IL-18- and sirtuin-1-independent pathways.

Li Ya-Feng YF Nanayakkara Gayani G Sun Yu Y Li Xinyuan X Wang Luqiao L Cueto Ramon R Shao Ying Y Fu Hangfei H Johnson Candice C Cheng Jiali J Chen Xiongwen X Hu Wenhui W Yu Jun J Choi Eric T ET Wang Hong H Yang Xiao-Feng XF

Journal of hematology & oncology 20170202 1

<h4>Background</h4>It is well established that caspase-1 exerts its biological activities through its downstream targets such as IL-1β, IL-18, and Sirt-1. The microarray datasets derived from various caspase-1 knockout tissues indicated that caspase-1 can significantly impact the transcriptome. However, it is not known whether all the 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 transcrip ...[more]

PMID: 28153032

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Project description:BackgroundHuman immunodeficiency virus (HIV) promotes an inflammatory process, leading to the progressive loss of the functional capacity of the immune system. The HIV infection induces alterations in several tissues, but mainly in the gut-associated lymphoid tissue (GALT). However, the degree of GALT deterioration varies among infected individuals. In fact, it has been shown that HIV-controllers, who spontaneously control viral replication, exhibit a lower inflammatory response, and a relative normal frequency and function of most of the immune cells. Inflammasomes are molecular complexes involved in the inflammatory response, being NLRP1, NLRP3, NLRC4, AIM2 and Pyrin inflammasomes, the best characterized so far. These complexes regulate the maturation of cytokines of the IL-1 family, including IL-1β and IL-18. These cytokines have been associated with immune activation and expansion of HIV target cells, promoting viral replication. Interesting, some reports indicate that HIV induces the activation of the NLRP3 inflammasome, but the role of this, and other inflammasomes during HIV infection, especially in GALT, remains unclear.ObjectiveTo compare the relative expression of inflammasome components and the proinflammatory response related to their activity, between HIV-progressors and HIV-controllers.MethodsGALT biopsies and peripheral blood mononuclear cells (PBMCs) from 15 HIV-controllers and 15 HIV-progressors were obtained. The relative expression of the following inflammasome components were evaluated by RT-PCR: NLRP3, NLRC4, NLRP1, AIM2, ASC, Caspase-1, IL-1β and IL-18. In addition, plasma concentration of IL-18 was evaluated as an indicator of baseline proinflammatory status. Finally, in supernatants of PBMCs in vitro stimulated with inflammasome agonists, the concentrations of IL-1β and IL-18 were quantified by ELISA.ResultsHIV-progressors exhibited higher expression of IL-1β, IL-18 and caspase-1 genes in GALT and PBMCs compared with HIV-controllers. In addition, HIV-progressors had also increased expression of ASC in PBMCs. When plasma levels were evaluated, IL-18 was increased in HIV-progressors. Interesting, these patients also showed an increased production of IL-1β in supernatants of PBMCs stimulated in vitro with the agonists of AIM2, NLRP1 and NLRC4 inflammasomes. Finally, the expression of caspase-1, NLRP1, IL-1β and IL-18 in GALT or peripheral blood was correlated with CD4+ T-cell count and viral load.ConclusionOur results suggest that during HIV-infection, the required signals to induce the expression of different components of the inflammasomes are produced, both in GALT and in periphery. The activation of these molecular complexes could increase the number of target cells, favoring HIV replication and cell death, promoting the disease progression.

Dataset Information

Analyses of caspase-1-regulated transcriptomes in various tissues lead to identification of novel IL-1?-, IL-18- and sirtuin-1-independent pathways.

Publications

Analyses of caspase-1-regulated transcriptomes in various tissues lead to identification of novel IL-1β-, IL-18- and sirtuin-1-independent pathways.

Similar Datasets

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