Signaling pathways associated with interleukins 12 and 23 and epigenetic mechanism of sequential-specific regulation of expression of related genes by miRNAs as molecular markers for assessing the potential of anti-cytokine therapies

Abstract

The molecular targeted therapy is focused on blocking the activity of specific cytokines and the signalling cascades they activate. In the treatment of psoriasis, this type of therapy is based on treatment with anti-tumor necrosis factor drugs, anti-IL-12/23, anti-IL-17, inhibitors of JAK kinases. Interleukins 12 and 23 interact with the receptors to trigger the JAK/STAT signalling pathway, the end products of which are other cytokines, e.g. tumour necrosis factor, IL-17, interferon g. These cytokines affect both IL-12/23 shaping their concentration profile, as well as trigger other signalling paths themselves. Gene expression is regulated by DNA methylation, miRNA molecules and histone protein modifications. The miRNA seems to be a promising model of a molecular marker system. Understanding the interrelationships between individual signalling pathways associated with IL-12 and IL-23 and the role of epigenetic mechanisms to regulate their expression is important for the development and implementation of new diagnostic-therapeutic schemes and the further development of personalized medicine. streszczenie Terapia ukierunkowana molekularnie skoncentrowana jest na blokowaniu aktywności określonych cytokin i aktywowanych przez nie kaskad sygnałowych. W łuszczycy opiera się ona na leczeniu wieloma grupami leków (leki anty-TNF, anty-IL-12/23, anty-IL-17, inhibitory kinaz JAK). Interleukiny 12 i 23 poprzez interakcje z receptorami uruchamiają ścieżkę sygnalizacyjną JAK/STAT, której Review aRticle/Praca Poglądowa signaling pathways associated with interleukins 12 and 23 and epigenetic mechanism of sequential-specific regulation of expression of related genes by mirnAs as molecular markers for assessing the potential of anti-cytokine therapies Ścieżki sygnalizacyjne związane z interleukiną 12 i 23 oraz epigenetyczny mechanizm sekwencyjnie specyficznej regulacji ekspresji związanych z nimi genów przez cząsteczki mirnA jako molekularne markery oceny potencjału terapii antycytokinowych

Expression of genes related to inflammation – IL-6, IL-8, and IFN-γ in monitoring ustekinumab therapy: preliminary results

“…Changes in the concentration profile of certain cytokines, such as IL-12, IL-23, IL-17, IL-6, IL-8 and IFN-γ, play an important role in the pathology of psoriasis, and the understanding of their mutual correlations and molecular relationships is a necessity to find an effective form of therapy [13].…”

“…Phosphorylation by STAT protein kinases enables their transport to the cell nucleus where they become transcription factors, thus influencing the expression of genes of various cytokines. This is an example of positive feedback, in which stimulation of a single signalling pathway affects the expression of other cytokines, stimulating inflammation and making it difficult to inhibit it [13].…”

“…This drug, compared to conventional treatment methods, according to the latest studies conducted by the Psoriasis Longitudinal Assessment and Registry (PSOLAR) [24] in Caucasian patients, as well as studies conducted by the Programme for Europe-Asia Research Linkages (PEARL) in Asian patients [25], is characterized by a high safety profile and a low risk of side effects in the form of malignant tumours, cardiovascular diseases, and overall mortality. As with other biological drugs used in the treatment of autoimmune and inflammatory diseases, however, the immunosuppressive effects of treatment should be considered, which may lead to an exacerbation of comorbidities, in particular viral and bacterial infections, liver diseases, or circulatory failure [13]. Ustekinumab is a drug directed against two inflammatory interleukins, IL-12 and IL-23, but its effects also indirectly affect other cytokines downstream in the inflammatory cascade [26].…”

“…Ustekinumab is a drug directed against two inflammatory interleukins, IL-12 and IL-23, but its effects also indirectly affect other cytokines downstream in the inflammatory cascade [26]. However, it is important not only to analyse one specific signalling pathway, but also to find links between different cascades of inflammatory reactions, activated by different cytokines, and to understand how they are regulated at the level of their gene expression [13].…”