Interferon gamma (IFNG), in a JAK1- and STAT1-dependent manner, transiently inhibits TGF-beta signaling by stimulating transcription of SMAD7, an inhibitor of TGF-beta receptor complex-mediated activation of SMAD2 and SMAD3 (Ulloa et al. 1999). IFNG-induced, JAK1- and STAT1- mediated upregulation was shown in human cells of fibroblast origin (U4A fibrosarcoma cell line) (Ulloa et al. 1999; Weng et al. 2007), leukocyte origin (U937 monocytic leukemia cell line) (Ulloa et al. 1999), keratinocyte origin (A431 epidermoid carcinoma cell line) (Ulloa et al. 1999), human bronchoepithelial cells (HBECs) (Wen et al. 2004), human gastric carcinoma cells (GCTM-1 cell line) (Kuga et al. 2003), and rat hepatic stellate cells (Weng et al. 2007). Direct binding of STAT1 to the SMAD7 gene promoter has not been demonstrated. IFNG-mediated attenuation of TGF-beta signaling may be involved in IFNG-mediated reduction of pulmonary (Wen et al. 2004) and hepatic (Weng et al. 2007) fibrosis.

In addition to IFN-gamma-mediated downregulation of TGF-beta signaling through induction of SMAD7 expression and interference of IFN-gamma signaling with expression of TGF-beta-activated collagen genes through IFN-gamma-activated transcription factor YBX1 (Dooley et al. 2006), the interplay between IFN-gamma signaling on TGF-beta signaling involves several other mechanisms of crosstalk that are currently not annotated. Some of these mechanisms are antagonistic, while other are synergistic, which appears to be context dependent. In human bronchoepithelial cells, IFNG reduces release of TGFB2, which is stimulated by TGFB1, TGFB3, IL1B, PDGF and IL4 (Wen et al. 2004). In human CD8+ T-cells, TGF-beta signaling induces expression of microRNAs that target the 3’UTR of IFNG mRNA, leading to attenuation of IFNG levels (Chandran et al. 2014). Similarly, TGF-beta limits the activation of human natural killer (NK) cells and reduces the amount of IFN-gamma produced by NK cells (Naganuma et al. 1996, Meadows et al. 2006). In B cells and other antigen-presenting cells, TGF-beta inhibits IFN-gamma-mediated, STAT1-dependent transcription of class II transactivator (CIITA), required for constitutive and IFN-gamma inducible expression of class II MHC genes (Nandan and Reiner 1997, Piskurich et al. 1998, Piskurich et al. 1999). In mouse B cells, IFN-gamma inhibits TGFB1-induced IgA secretion (Park et al. 2010). In vascular smooth muscle cells, TGF-beta and IFN-gamma antagonistically regulate expression of splice variants of the RFXANK (RFXB) gene that have opposing effects on the recruitment of HDAC2 to the collagen gene COL1A2 (Fang et al. 2009). In regulatory T cells, IFNG amplifies TGF-beta-induced expression of the FOXP3 gene, a master regulator of development and function of regulatory T cells (Ouaked et al. 2009). In human corneal stromal fibroblasts, IFN-gamma induces expression of higher affinity TGF-beta receptors, which is proposed to enhance corneal immunoseclusion in order to maintain corneal optical transparency (Abrahamian et al. 1994). In human retinal pigment epithelium, IFN-gamma increases TGFB1 mRNA levels, but reduces TGFB2 mRNA levels (Nagineni et al. 2007).