Role of interferon-gamma (IFN-?) and IFN-? receptor 1/2 (IFN?R1/2) in regulation of immunity, infection, and cancer development: IFN-?-dependent or independent pathway

IFN-??, a soluble cytokine being produced by T lymphocytes, macrophages, mucosal epithelial cells, or natural killer cells, is able to bind to the IFN-?? receptor (IFN??R) and in turn activate the Janus kinase (JAK)-signal transducer and transcription protein (STAT) pathway and induce expression of IFN-??-stimulated genes. IFN-?? is critical for innate and adaptive immunity and aberrant IFN-?? expression and functions have been associated with different human diseases. However, the IFN-??/IFN??R signaling could be a double-edged sword in cancer development because the tissue microenvironments could determine its anti-or pro-tumorigenic activities. The IFN??R protein consists of two IFN??R1 and IFN??R2 chains, subunits of which play different roles under certain conditions. This review assessed IFN??R polymorphisms, expression and functions in development and progres-sion of various human diseases in an IFN-??-dependent or independent manner. This review also discussed tumor microenvironment, microbial infection, and vital molecules in the IFN-?? upstream signaling that might regulate IFN??R expression, drug resistance, and druggable strategy, to provide evidence for further application of IFN??R.

Automated summary

IFN-?? is a soluble cytokine that activates the JAK-STAT pathway to induce expression of IFN-??-stimulated genes, playing critical roles in innate and adaptive immunity. However, its role in cancer development is complex and depends on the tissue microenvironment. This review evaluates the polymorphisms, expression, and functions of IFN??R in various human diseases and discusses factors that regulate IFN??R expression, drug resistance, and therapeutic strategies.