Differential Effect of JAK1/2 and TYK2 Inhibitors on Type III Interferon Induced Antiviral Defence in Human Intestinal Epithelial Cells

Abstract

Introduction: Many cytokines, acting via Janus kinase (JAK)/tyrosine kinase 2 (TYK2)/signal transducer and activator of transcription (STAT) signalling pathways, are critical mediators of pathology in immune-mediated inflammatory diseases (IMIDs). Therefore, drugs that inhibit JAKs and TYKs (JAKis) have gained traction as effective treatment options for IMIDs. However, a common side effect of JAKis is increased risk of viral infection. Type I and III interferon (IFN) signal via JAK1 and TYK2. Type III IFNs protect mucosal membranes, including the intestinal barrier, from viral infection and type I IFNs prevent systemic viral spread. Methods: The human cell lines Caco-2 and HT-29 were used to investigate the impact of currently approved JAKis, baricitinib (JAK1/2 inhibitor) and deucravacitinib (TYK2 inhibitor), on type I and III IFN signalling and antiviral defence of intestinal epithelial cells (IECs). Results: Using concentrations commonly used for in vitro studies on IFNs, we found that attenuation of IFN-mediated antiviral defence in IECs is a mechanism that could contribute to the increased risk of viral infections associated with JAKis. However, when we examined clinically relevant drug concentrations, we found that while both drugs blocked the type I IFN response, type III IFN-induced antiviral immunity was less affected during TYK2 inhibition (deucravacitinib) compared to JAK1/2 inhibition (baricitinib). Conclusions: Our studies suggest that in treating diseases associated with excessive cytokine production (e.g., type I IFNs, interleukin (IL)-6, and IL-23), a TYK2 inhibitor may be preferable over a JAK1/2 inhibitor. This preference arises as the TYK2 inhibitor can effectively block the activity of proinflammatory and tissue-damaging cytokines (e.g., type I IFNs), while having less negative impact on the intestine’s ability to respond to type III IFN, thereby enabling it to enter an antiviral state.