A method for the inference of cytokine interaction networks

Cell-cell communication is mediated by many soluble mediators, including over 40 cytokines. Cytokines, e.g. TNF, IL1β, IL5, IL6, IL12 and IL23, represent important therapeutic targets in immune-mediated inflammatory diseases (IMIDs), such as inflammatory bowel disease (IBD), psoriasis, asthma, rheumatoid and juvenile arthritis. The identification of cytokines that are causative drivers of, and not just associated with, inflammation is fundamental for selecting therapeutic targets that should be studied in clinical trials. As in vitro models of cytokine interactions provide a simplified framework to study complex in vivo interactions, and can easily be perturbed experimentally, they are key for identifying such targets. We present a method to extract a minimal, weighted cytokine interaction network, given in vitro data on the effects of the blockage of single cytokine receptors on the secretion rate of other cytokines. Existing biological network inference methods typically consider the correlation structure of the underlying dataset, but this can make them poorly suited for highly connected, non-linear cytokine interaction data. Our method uses ordinary differential equation systems to represent cytokine interactions, and efficiently computes the configuration with the lowest Akaike information criterion value for all possible network configurations. It enables us to study indirect cytokine interactions and quantify inhibition effects. The extracted network can also be used to predict the combined effects of inhibiting various cytokines simultaneously. The model equations can easily be adjusted to incorporate more complicated dynamics and accommodate temporal data. We validate our method using synthetic datasets and apply our method to an experimental dataset on the regulation of IL23, a cytokine with therapeutic relevance in psoriasis and IBD. We validate several model predictions against experimental data that were not used for model fitting. In summary, we present a novel method specifically designed to efficiently infer cytokine interaction networks from cytokine perturbation data in the context of IMIDs.Author summary: Cytokines are the messenger molecules of the immune system, allowing intercellular communication and mediating effective immune responses. They are an important therapeutic target in immune mediated inflammatory diseases such as inflammatory bowel disease (IBD) and rheumatoid arthritis. Cytokines interact in a tightly regulated network and depending on the context a particular cytokine can be involved in anti-inflammatory or inflammatory activities. In order to determine which cytokines to target in specific disease types and patient subsets, it is critical to study the effects of the inhibition of one or more cytokines on the larger cytokine interaction network. We present a novel method to extract a minimal, weighted network from cytokine interaction data. Existing biological network inference methods typically consider the correlation structure of the underlying dataset and/or make further assumptions of the dataset such as the existence of a small core of regulators. This can make them poorly suited for highly connected, non-linear cytokine interaction data. We validated our method using synthetic data and applied our method to a dataset on the regulation of IL23, a cytokine implicated in IBD pathogenesis. Predictions of the extracted IL23 network were validated using additional experimental data and were used to support the view of the cytokines IL1 and IL23 as promising targets for those patients that fail to respond to TNFα inhibition, the current golden standard in IBD treatment.