negative regulation of interleukin-2-mediated signaling pathway

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of interleukin-2-mediated signaling pathway. [GOC:TermGenie, PMID:11909529]

Negative regulation of interleukin-2 (IL-2)-mediated signaling pathway is a complex process involving multiple cellular and molecular mechanisms that dampen the intensity and duration of IL-2 signaling. This regulation is crucial to maintain immune homeostasis and prevent excessive immune activation, which can lead to autoimmune disorders or uncontrolled inflammation.

IL-2 signaling is initiated when IL-2 binds to its receptor (IL-2R) on the surface of immune cells, primarily T lymphocytes. This binding triggers a cascade of intracellular events that ultimately lead to the activation of transcription factors, such as NF-κB and STAT5, which induce the expression of genes involved in T cell proliferation, differentiation, and survival.

Negative regulation of IL-2 signaling occurs at various levels:

1. **Receptor Downregulation:** IL-2R expression can be downregulated by various mechanisms, including endocytosis and degradation of the receptor. This reduces the availability of IL-2 receptors on the cell surface, limiting IL-2 binding and subsequent signaling.

2. **Inhibition of Signal Transduction:** Several intracellular molecules act as negative regulators of IL-2 signaling by inhibiting the activation of downstream signaling pathways. These include:
* **Protein tyrosine phosphatases (PTPs):** These enzymes dephosphorylate key signaling proteins, such as JAK3 and STAT5, preventing their activation.
* **Suppressor of cytokine signaling (SOCS) proteins:** These proteins inhibit the JAK/STAT signaling pathway by blocking the phosphorylation of JAK kinases and promoting the degradation of STAT5.
* **SH2-containing protein tyrosine phosphatase 1 (SHP-1):** This phosphatase dephosphorylates and inactivates various signaling molecules involved in IL-2 signaling, including the IL-2R itself.

3. **Production of Inhibitory Cytokines:** Certain cytokines, such as IL-10 and TGF-β, can suppress IL-2 production and signaling. They achieve this by inhibiting the activation of T cells and promoting the differentiation of regulatory T cells (Tregs), which actively suppress immune responses.

4. **Induction of Anergy:** Prolonged exposure to IL-2 in the absence of other costimulatory signals can lead to a state of anergy, where T cells become unresponsive to IL-2 stimulation. Anergy is characterized by the downregulation of IL-2R expression and the upregulation of inhibitory molecules.

5. **Activation of Cell Death Pathways:** In some cases, excessive IL-2 signaling can trigger apoptosis (programmed cell death) of T cells. This mechanism serves as a failsafe to prevent uncontrolled T cell proliferation.

The intricate network of negative regulators ensures that IL-2 signaling is tightly controlled, preventing excessive immune activation and maintaining immune homeostasis. Dysregulation of IL-2 signaling has been implicated in various autoimmune diseases, cancer, and infectious diseases. Therefore, understanding the mechanisms of negative regulation of IL-2 signaling is crucial for developing therapeutic strategies for these conditions.'
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