regulation of response to type II interferon

Definition

Target type: biologicalprocess

Any process that modulates the rate, frequency or extent of a response to type II interferon (interferon-gamma). Response to interferon gamma is a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of an interferon-gamma stimulus. [GOC:dph]

Type II interferons (IFN-γ) are crucial cytokines that play a central role in the immune response against intracellular pathogens, including viruses, bacteria, and parasites. The regulation of response to type II interferon involves a complex interplay of signaling pathways, transcription factors, and target genes, ultimately orchestrating a multifaceted cellular response aimed at eliminating the invading pathogen.

The process begins with the binding of IFN-γ to its receptor, IFNGR, a heterodimeric complex composed of IFNGR1 and IFNGR2 subunits. This binding event triggers the activation of the JAK-STAT signaling pathway. Janus kinases (JAKs), specifically JAK1 and JAK2, associated with the IFNGR complex, are phosphorylated upon ligand binding. Phosphorylated JAKs then activate the signal transducer and activator of transcription (STAT) proteins, predominantly STAT1 and STAT2. These STATs are phosphorylated by JAKs and subsequently dimerize, forming the IFN-γ-activated factor (GAF) complex. GAF translocates to the nucleus and binds to specific DNA sequences, known as IFN-γ-activated sites (GAS), located in the promoter regions of target genes.

The binding of GAF to GAS initiates the transcription of a diverse array of genes involved in the antiviral, antibacterial, and antiparasitic responses. These genes include:

* **Immune effector molecules:** Interferon-stimulated genes (ISGs) like Mx1, PKR, and OAS1, which directly inhibit viral replication.
* **Cytokines and chemokines:** Interleukin-12 (IL-12) and CXCL10, which promote Th1 cell differentiation and leukocyte recruitment to the infected site.
* **Antigen presentation molecules:** Major histocompatibility complex (MHC) class I and II, which enhance antigen presentation to CD8+ and CD4+ T cells, respectively.
* **Apoptosis-related genes:** Fas ligand (FasL) and TRAIL, which induce apoptosis in infected cells to limit pathogen spread.

The regulation of response to type II interferon is further fine-tuned by a variety of mechanisms, including:

* **Negative feedback loops:** SOCS proteins, induced by IFN-γ signaling, inhibit JAK activity and attenuate the response, preventing excessive activation.
* **Cross-regulation with other signaling pathways:** IFN-γ signaling can interact with and influence other pathways, such as the TLR pathway and the NF-κB pathway, further modulating the immune response.
* **Epigenetic modifications:** Histone modifications and DNA methylation can influence the accessibility of GAS elements, fine-tuning gene expression in response to IFN-γ.

In summary, the regulation of response to type II interferon is a complex and dynamic process involving multiple signaling pathways, transcription factors, and target genes. This intricate network ensures that the immune response is tailored to the specific pathogen and the cellular context, ultimately contributing to the successful elimination of the infection.'
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