positive regulation of interleukin-6-mediated signaling pathway

Definition

Target type: biologicalprocess

Any process that increases the rate, frequency or extent of an interleukin-6-mediated signaling pathway. [GOC:BHF, GOC:mah]

Positive regulation of interleukin-6 (IL-6)-mediated signaling pathway is a complex biological process involving multiple steps and molecular players. It is initiated when IL-6 binds to its receptor, IL-6R, on the cell surface. This binding triggers the activation of a signaling cascade that leads to the activation of various downstream transcription factors, ultimately influencing gene expression and cellular function.

The key steps in this process include:

1. **Ligand Binding and Receptor Dimerization:** IL-6 binds to its receptor, IL-6R, which exists as a monomer on the cell surface. This binding event induces a conformational change in IL-6R, allowing it to associate with the glycoprotein 130 (gp130) protein. gp130 acts as a signal transducer and is shared by other cytokine receptors, including IL-11, IL-27, and ciliary neurotrophic factor (CNTF). This association leads to the formation of a hexameric complex consisting of two IL-6 molecules, two IL-6R molecules, and two gp130 molecules.

2. **Activation of Janus Kinases (JAKs):** The formation of the hexameric complex brings together the intracellular domains of gp130. These domains contain binding sites for Janus kinases (JAKs), specifically JAK1 and JAK2. The association of gp130 with JAKs leads to their activation, resulting in autophosphorylation and the recruitment of downstream signaling molecules.

3. **Phosphorylation and Activation of Signal Transducer and Activator of Transcription (STAT) Proteins:** Activated JAKs phosphorylate tyrosine residues on the intracellular tails of gp130. These phosphorylated tyrosine residues serve as docking sites for members of the STAT family of transcription factors, specifically STAT1, STAT3, and STAT5. The binding of STAT proteins to phosphorylated gp130 leads to their phosphorylation by JAKs, resulting in their dimerization and translocation into the nucleus.

4. **Gene Transcription and Cellular Response:** Once in the nucleus, activated STAT dimers bind to specific DNA sequences in the promoters of target genes, initiating their transcription. These genes encode proteins that mediate a wide range of biological responses, including cell proliferation, differentiation, inflammation, and immune regulation.

5. **Negative Regulation:** The IL-6 signaling pathway is tightly regulated to ensure its appropriate activation and prevent excessive or prolonged signaling. Negative feedback mechanisms include the activation of suppressors of cytokine signaling (SOCS) proteins, which inhibit JAK activity, and the recruitment of protein tyrosine phosphatases (PTPs), which dephosphorylate and inactivate STAT proteins.

In addition to the core signaling pathway described above, IL-6 can also activate other signaling pathways, including the mitogen-activated protein kinase (MAPK) pathway and the phosphoinositide 3-kinase (PI3K)/Akt pathway, contributing to a broader range of cellular responses.

The positive regulation of IL-6 signaling pathway plays a critical role in various physiological processes, including inflammation, immune responses, and hematopoiesis. However, dysregulation of this pathway is implicated in various pathological conditions, including autoimmune diseases, cancer, and inflammatory bowel disease. Therefore, understanding the molecular mechanisms underlying IL-6 signaling is essential for developing therapeutic strategies targeting this pathway.'
"

Proteins (1)

Compounds (82)