An assembled molecular signaling map of interleukin-24: a resource to decipher its multifunctional immunoregulatory role in pathophysiological conditions

Abstract

Introduction: Interleukin-24 (IL-24) is a cytokine belonging to the IL-10 family with immunoregulatory properties. It is known to induce cellular responses in various disease conditions, including inflammatory, infectious diseases, and cancer, in a receptor-dependent and independent manner. IL-24 is induced by both immune and non-immune cells and acts on a vast array of target cells to regulate various biological processes. The antitumor and immunoregulatory properties of IL-24 support its application as a therapeutic agent in a vast array of pathological conditions. Characterizing the molecular events associated with its immunomodulatory properties is essential for evaluating its utility in cancer immunotherapy.

Methods: The data related to signaling events induced by IL-24 were then manually annotated and cataloged from the literature pertaining to IL-24 signaling. The cataloged molecular events were then manually drawn based on the topology as a signaling pathway map of IL-24.

Results: Based on the data mined from published literature, we assembled IL-24-regulated signaling events linked to its immunoregulatory and anti-tumor activities. The receptor-ligand interaction of IL-24 regulates multiple downstream signaling cascades, leading to antitumor activities alongside inducing inflammatory reactions and anti-infectious processes. We provide a signaling pathway map of IL-24 consisting of 433 mRNAs/proteins and their 613 signaling events.

Discussion: We believe this map would serve as a knowledge base for reference and one-go visualization of the signaling events identified to be induced by IL-24. Moreover, this map is made available (https://ciods.in/il24/) for the researchers to explore the role of IL-24 in various pathophysiological conditions through the gene set enrichment of transcriptomics or proteomics datasets from various disease conditions.

Keywords: immune cells; immuno-stimulation; signaling pathway; therapeutic agent; tumor suppressor cytokine.

Figure 1

A detailed workflow outlining the methodology for the IL-24 signaling pathway data curation, annotation, and map development. The workflow depicts the sequential steps used to develop the IL-24 signaling pathway map. The literature related to IL-24 signaling in cancer, infectious, and inflammatory disease conditions was manually screened, followed by the curation and annotation of the signaling events according to the NetPath criteria. Further, with the annotated data, a detailed signaling pathway map was developed.

Figure 2

The schematic representation of IL-24-induced signaling reactions. The signaling pathway map shows molecules associated with ligand-receptor interactions and IL-24 downstream molecular events. The pathway comprises the signaling modules such as activation/inhibition, enzyme catalysis, protein/gene regulatory events, molecular association, and translocation events induced by IL-24 toward its anti-tumor and immunoregulatory properties. These signaling events are represented with a specific type of edge and are color-coded as mentioned in the pathway legend. The pathway also includes information about the site and residues of post-translational modifications. The functions/processes linked to each signaling event, as annotated from the curated study, are displayed at the bottom of the pathway.

Figure 3

Diagrammatic illustration of the synergistic activity of IL-24 along with the various drugs and therapeutic agents. The diagram summarizes the synergistic action of IL-24 and other pharmacological agents in various disease conditions. Key drugs and the cancer conditions indicated in the study are represented along with the amplified therapeutic responses.

Figure 4

Protein-protein interaction network analysis. The figure represents the interaction network analysis of IL-24, its receptors, and downstream targets. The proteins are color-coded according to five distinct clusters based on the hub genes analysis. The hub genes are highlighted within each cluster, and the blue colored nodes depict the proteins that interact directly or indirectly with these hub genes.