Tumor necrosis factor-mediated interferon signaling pathway (TNF-IFN signaling)

The Tumor necrosis factor (TNF)-mediated interferon (IFN) signaling pathway is a complex regulatory network where TNF signaling intersects with IFN responses to coordinate immune activity (Yarilina et al., 2008, J Exp Med). TNF can stimulate the production of Type I interferons (IFN-α/β) via the activation of interferon regulatory factors (IRFs) or sensitize cells to IFN-mediated signaling through the JAK/STAT pathway (Ivashkiv, 2018, Nat Rev Immunol). This pathway plays a pivotal role in the synergistic induction of inflammatory genes and the execution of programmed cell death, including apoptosis and necroptosis, often referred to as panoptosis (Karki et al., 2021, Cell). In healthy states, this crosstalk is essential for host defense against pathogens; however, chronic overactivation is a hallmark of autoimmune diseases like rheumatoid arthritis and inflammatory bowel disease (McInnes & Schett, 2011, N Engl J Med). Therapeutic intervention typically targets specific nodes within the pathway, such as TNF-α itself using monoclonal antibodies like adalimumab or downstream signaling using Janus kinase (JAK) inhibitors (Salomon et al., 2017, Pharmacol Rev). Monitoring biomarkers like CXCL10 or STAT1 phosphorylation can help assess the activity of this pathway in clinical settings, though safety concerns include an increased risk of serious infections and tuberculosis reactivation (Lee et al., 2021, Nat Rev Rheumatol). This axis is also a major focus in understanding cytokine storms associated with severe viral infections, where the TNF-IFN synergy drives systemic tissue damage (Karki et al., 2021, Cell). Overall, the pathway represents a critical target for immunomodulatory therapies aimed at balancing protective immunity and pathological inflammation.

Other names

TNF-IFN crosstalkTNF-IFN axisTNF-induced interferon productionTNF-IFN synergistic signaling

Neutralization of TNF-alpha or inhibition of downstream JAK/STAT signaling to disrupt the synergistic inflammatory and cell death signaling between TNF and interferons.