Interferon gamma signaling pathway (IFN-gamma pathway)

The endogenous interferon gamma (IFN-gamma) pathway is a critical signaling cascade in the immune system, primarily mediated by the type II interferon, IFN-gamma. This pathway is initiated when IFN-gamma, a homodimeric cytokine produced by activated T cells and natural killer (NK) cells, binds to its cell-surface receptor (IFNGR), which consists of IFNGR1 and IFNGR2 subunits. Ligand binding triggers the activation of the Janus kinases JAK1 and JAK2, leading to the phosphorylation and dimerization of the Signal Transducer and Activator of Transcription 1 (STAT1). The STAT1 homodimers then translocate to the nucleus to induce the transcription of numerous interferon-stimulated genes (ISGs) involved in antiviral defense, MHC expression, and macrophage activation. In disease, dysregulation of the IFN-gamma pathway is linked to various conditions; overactivity is associated with autoimmune disorders and hemophagocytic lymphohistiocytosis (HLH), while impaired signaling can lead to increased susceptibility to intracellular pathogens and cancer progression. Therapeutic strategies targeting this pathway include the use of recombinant IFN-gamma (Interferon gamma-1b) to enhance immune responses in chronic granulomatous disease, and neutralizing antibodies like emapalumab to treat HLH. Additionally, small molecule inhibitors of the downstream JAK kinases are widely used to treat inflammatory and myeloproliferative diseases by dampening the pathway's signaling.

Other names

Type II interferon signaling pathwayIFN-gamma/JAK/STAT pathwayEndogenous IFN-gamma pathwayIFNG pathway

Neutralization of the IFN-gamma ligand, agonism of the IFN-gamma receptor, and inhibition of downstream JAK1/2 kinases or STAT1 activation.