Investigation of the Effects of TBK1 Inhibitors on the Inflammatory Response in Lymphocytes of Cases Diagnosed with Inflammatory Bowel Disease
Project no. 33071 · Status: Kapanmış (Yayın bekleniyor) · 2025
Summary
<p>Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder of the gastrointestinal tract that is primarily classified into two major subtypes: ulcerative colitis (UC), which is characterized by inflammation limited to the colonic mucosa, and Crohn's disease (CD), which can affect any segment of the gastrointestinal tract. In recent years, the incidence of pediatric and adolescent IBD has increased markedly worldwide. Pediatric-onset disease is generally associated with a more aggressive clinical course than adult-onset IBD and is frequently accompanied by severe complications, including growth retardation, anemia, and perianal disease. Although the molecular mechanisms underlying IBD have not yet been fully elucidated, accumulating evidence suggests that excessive activation of the cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS–STING) signaling pathway contributes to the disruption of intestinal homeostasis by promoting the production of pro-inflammatory cytokines and type I interferons. Tank-Binding Kinase 1 (TBK1), a serine/threonine kinase located at the center of this signaling cascade, undergoes trans-autophosphorylation following cGAMP-mediated STING activation and subsequently phosphorylates interferon regulatory factor 3 (IRF3), thereby initiating the transcription of type I interferon genes. Therefore, inhibition of TBK1, a critical mediator of cGAS–STING signaling, has emerged as a promising therapeutic strategy for IBD through suppression of downstream inflammatory signaling, ultimately reducing mucosal inflammation and tissue injury.</p><p>In the present study, peripheral blood samples were collected from pediatric patients diagnosed with IBD and healthy volunteers, and peripheral blood mononuclear cells (PBMCs) were isolated. PBMCs were treated with the TBK1 inhibitors Amlexanox (AMX) and MRT67307 (MRT), and the effects of these compounds on interferon-related gene expression were investigated. The mRNA expression levels of IFIT2, IFI44, and ISG15 were quantified using quantitative real-time polymerase chain reaction (qRT-PCR).</p><p>The results demonstrated that the expression levels of IFIT2, IFI44, and ISG15 were significantly higher in PBMCs obtained from pediatric IBD patients than in those from healthy controls. Although a trend toward reduced IFIT2 and IFI44 expression was observed following treatment with AMX and MRT, these reductions did not reach statistical significance. Likewise, no significant change in ISG15 expression was detected after inhibitor treatment. Collectively, these findings suggest that interferon-associated signaling pathways are activated in pediatric IBD and that TBK1 inhibition may contribute to the regulation of this inflammatory response. However, further studies involving larger patient cohorts together with protein-level analyses are required to validate these observations and to clarify the therapeutic potential of TBK1 inhibition in inflammatory bowel disease.</p>