negative regulation of interleukin-17 production

Definition

Target type: biologicalprocess

Any process that stops, prevents, or reduces the frequency, rate, or extent of production of any member of the interleukin-17 family of cytokines. [GOC:add, GOC:mah, PMID:16482511]

Negative regulation of interleukin-17 (IL-17) production is a crucial process for maintaining immune homeostasis and preventing excessive inflammation. IL-17 is a pro-inflammatory cytokine primarily produced by T helper 17 (Th17) cells, playing a critical role in host defense against extracellular pathogens. However, dysregulation of IL-17 production can contribute to various autoimmune and inflammatory diseases. The negative regulation of IL-17 production involves multiple mechanisms at different levels, including:

**1. Transcriptional Regulation:**

* **Suppression of Th17 Cell Differentiation:**
* **Transcription factors:** Transcription factors like Foxp3 (expressed in regulatory T cells, Tregs), GATA3 (expressed in Th2 cells), and Runx3 (expressed in Th1 cells) can suppress the expression of RORγt, a master regulator of Th17 cell differentiation.
* **Cytokines:** IL-2, IL-4, and IL-10, produced by Tregs and other immune cells, inhibit the differentiation of Th17 cells by blocking RORγt expression and promoting the expression of other transcription factors like Foxp3.
* **Inhibition of IL-17 Gene Expression:**
* **MicroRNAs:** MicroRNAs like miR-146a and miR-155 can directly target and suppress the expression of IL-17 mRNA.
* **Histone modifications:** Histone modifications, such as deacetylation and methylation, can alter chromatin structure and restrict access of transcription factors to the IL-17 gene promoter, thus reducing its expression.

**2. Post-transcriptional Regulation:**

* **mRNA Stability:** Proteins like AU-rich element-binding protein 1 (AUF1) can bind to the 3'-UTR of IL-17 mRNA and promote its degradation, leading to reduced IL-17 protein production.
* **Protein Translation:** MicroRNAs can also target the 3'-UTR of IL-17 mRNA and interfere with its translation into protein.

**3. Post-translational Regulation:**

* **IL-17 Secretion Inhibition:** IL-17 is secreted by Th17 cells through exocytosis. Proteins like Rab27a and Rab27b, involved in vesicle trafficking, can regulate the secretion of IL-17.
* **IL-17 Signaling Inhibition:** IL-17 binds to its receptor, IL-17RA, initiating downstream signaling pathways. Molecules like soluble IL-17 receptor (sIL-17R) can act as decoys, binding to IL-17 and preventing it from activating its receptor.

**4. Immune Cell Interactions:**

* **Treg Cell Suppression:** Tregs can suppress the activity of Th17 cells through mechanisms like cell-cell contact, production of inhibitory cytokines (IL-10, TGF-β), and expression of cytotoxic molecules (granzyme B).
* **Other Immune Cells:** Macrophages, dendritic cells, and natural killer cells can also contribute to the negative regulation of IL-17 production through the production of cytokines and other regulatory molecules.

**5. Anti-inflammatory Mediators:**

* **IL-10:** IL-10 is a potent anti-inflammatory cytokine that suppresses the production of IL-17 and other pro-inflammatory cytokines.
* **TGF-β:** TGF-β is another anti-inflammatory cytokine that can promote the differentiation of Tregs, which in turn suppress Th17 cell activity.

**Conclusion:**

The negative regulation of IL-17 production is a complex process involving multiple pathways and mechanisms. Dysregulation of this process can contribute to the pathogenesis of various inflammatory and autoimmune diseases. Therefore, understanding the precise mechanisms involved in IL-17 suppression is essential for developing targeted therapies for these conditions.'
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Proteins (3)

Compounds (19)