negative regulation of interleukin-4-mediated signaling pathway

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of interleukin-4-mediated signaling pathway. [GOC:TermGenie, PMID:17210636]

Negative regulation of interleukin-4 (IL-4)-mediated signaling pathway involves a complex interplay of molecular mechanisms aimed at attenuating the cellular responses triggered by IL-4 binding to its receptor (IL-4R). This intricate process is crucial for maintaining immune homeostasis and preventing excessive or inappropriate immune activation. Here's a detailed description of the key players and steps involved:

1. **IL-4 Receptor (IL-4R) Dimerization and Signal Transduction:** IL-4 binding to IL-4R initiates a cascade of events. IL-4R is composed of two subunits, IL-4Rα and γc, and their association forms a functional receptor complex. Upon IL-4 binding, IL-4R dimerizes, triggering phosphorylation of tyrosine residues within the cytoplasmic domains of the receptor subunits. These phosphorylated tyrosine residues serve as docking sites for adaptor proteins like Janus kinase 1 (JAK1) and JAK3.

2. **JAK Kinase Activation and STAT6 Phosphorylation:** JAK1 and JAK3, once recruited to the phosphorylated receptor, undergo autophosphorylation and become activated. Activated JAK kinases then phosphorylate signal transducer and activator of transcription 6 (STAT6) on tyrosine residues. This phosphorylation event enables STAT6 dimerization and translocation into the nucleus.

3. **STAT6-Mediated Gene Transcription:** Nuclear translocation of STAT6 dimers facilitates their binding to specific DNA sequences known as STAT6 response elements present in the regulatory regions of IL-4-responsive genes. This binding initiates transcription of target genes, ultimately leading to downstream cellular responses.

4. **Negative Regulation Mechanisms:**
* **Suppression of JAK-STAT Pathway Activity:** Several mechanisms contribute to the suppression of JAK-STAT signaling. These include:
* **Protein Tyrosine Phosphatases (PTPs):** PTPs like SHP-1 and SHP-2 act as negative regulators by dephosphorylating JAK kinases, effectively dampening their activity.
* **Suppressor of Cytokine Signaling (SOCS) Proteins:** SOCS proteins, particularly SOCS1 and SOCS3, are induced by IL-4 signaling itself. They act as inhibitors of JAK kinase activity and also promote the degradation of IL-4R through ubiquitination.
* **Cytokine-Inducible SH2-Containing Protein (CIS):** CIS acts similarly to SOCS proteins, inhibiting JAK activity and promoting IL-4R degradation.
* **Modulation of IL-4R Expression:**
* **Downregulation of IL-4R Expression:** Negative feedback mechanisms can reduce IL-4R expression on the cell surface, limiting IL-4 responsiveness.
* **Alternative Splicing of IL-4Rα:** IL-4Rα undergoes alternative splicing, generating isoforms with altered signaling properties. Some isoforms might exhibit reduced affinity for IL-4 or impaired signal transduction.
* **Ubiquitination and Proteasomal Degradation:** IL-4R and other signaling components can be targeted for ubiquitination, marking them for degradation by the proteasome, effectively diminishing signaling.

5. **Cellular Responses Attenuation:** The negative regulatory mechanisms ultimately lead to the attenuation of IL-4-mediated signaling. This reduces the expression of IL-4-responsive genes, preventing excessive or prolonged activation of downstream pathways and ensuring proper immune function.

6. **Immune Homeostasis and Disease Prevention:** The intricate balance between IL-4 signaling and its negative regulation is critical for maintaining immune homeostasis. Dysregulation of these pathways can contribute to various immune disorders, such as allergies, asthma, and autoimmunity.

The negative regulation of IL-4-mediated signaling pathway is a highly dynamic process, involving a complex network of molecular interactions. By fine-tuning IL-4 signaling, these mechanisms play a crucial role in maintaining appropriate immune responses and preventing excessive or inappropriate immune activation.'"

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Compounds (30)