These models display abnormally low amounts of cells or necrosis of decidua.In humans, elevated levels of IFN-γ have been associated with increased risk of miscarriage. Correlation studies have observed high IFN-γ levels in women with a history of spontaneous miscarriage, when compared to women with no history of spontaneous miscarriage. Additionally, low-IFN-γ levels are associated with women who successfully carry to term. It is possible that IFN-γ is cytotoxic to trophoblasts, which leads to miscarriage. However, causal research on the relationship between IFN-γ and miscarriage has not been performed due to ethical constraints. Production
Recombinant human IFN-γ, as an expensive biopharmaceutical, has been expressed in different expression systems including prokaryotic, protozoan, fungal (yeasts), plant, insect and mammalian cells. Human IFN-γ is commonly expressed in Escherichia coli, marketed as ACTIMMUNE®, however, the resulting product of the prokaryotic expression system is not glycosylated with a short half-life in the bloodstream after injection; the purification process from bacterial expression system is also very costly. Other expression systems like Pichia pastoris did not show satisfactory results in terms of yields. Therapeutic use
Interferon-γ 1b is approved by the U.S. Food and Drug Administration to treat chronic granulomatous disease (CGD) and osteopetrosis. The mechanism by which IFN-γ benefits CGD is via enhancing the efficacy of neutrophils against catalase-positive bacteria by correcting patients oxidative metabolism.It was not approved to treat idiopathic pulmonary fibrosis (IPF).
IFN-γ is also produced by non-cytotoxic innate lymphoid cells (ILC), a family of immune cells first discovered in the early 2010s. Structure
The IFN-γ monomer consists of a core of six α-helices and an extended unfolded sequence in the C-terminal region. This is shown in the structural models below. The α-helices in the core of the structure are numbered 1 to 6. The biologically active dimer is formed by anti-parallel inter-locking of the two monomers as shown below. In the cartoon model, one monomer is shown in red, the other in blue. Receptor binding
Cellular responses to IFN-γ are activated through its interaction with a heterodimeric receptor consisting of Interferon gamma receptor 1 (IFNGR1) and Interferon gamma receptor 2 (IFNGR2). IFN-γ binding to the receptor activates the JAK-STAT pathway. Activation of the JAK-STAT pathway induces upregulation of interferon-stimulated genes (ISGs), including MHC II. IFN-γ also binds to the glycosaminoglycan heparan sulfate (HS) at the cell surface. However, in contrast to many other heparan sulfate binding proteins, where binding promotes biological activity, the binding of IFN-γ to HS inhibits its biological activity.The structural models shown in figures 1-3 for IFN-γ are all shortened at their C-termini by 17 amino acids. Full length IFN-γ is 143 amino acids long, the models are 126 amino acids long. Affinity for heparan sulfate resides solely within the deleted sequence of 17 amino acids. Within this sequence of 17 amino acids lie two clusters of basic amino acids termed D1 and D2, respectively. Heparan sulfate interacts with both of these clusters.