Page last updated: 2024-10-24

negative regulation of T-helper 17 cell lineage commitment

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of T-helper 17 cell lineage commitment. [GOC:BHF, GOC:mah]

Negative regulation of T-helper 17 cell lineage commitment is a crucial process that prevents excessive inflammation and autoimmune responses. This intricate process involves a complex interplay of signaling pathways, transcription factors, and epigenetic modifications.

**1. Inhibition of Th17-inducing signals:**
* **TGF-β signaling:** Transforming growth factor-beta (TGF-β) is a key cytokine involved in Th17 cell differentiation. Its signaling pathway is negatively regulated by various mechanisms, including:
* **SMAD7:** A negative regulator of TGF-β signaling that inhibits SMAD2/3 phosphorylation and downstream target gene activation.
* **IL-27:** This cytokine suppresses TGF-β-mediated Th17 differentiation by inducing the expression of STAT1, which competes with SMAD4 for binding to SMAD3, thereby inhibiting TGF-β signaling.
* **IL-6 signaling:** Interleukin-6 (IL-6) is another crucial cytokine for Th17 differentiation. Negative regulation of IL-6 signaling can occur through:
* **SOCS3:** Suppressor of cytokine signaling 3 (SOCS3) inhibits JAK/STAT signaling by binding to activated JAK kinases, preventing further phosphorylation of STAT3.
* **IL-27:** IL-27 can also suppress IL-6 signaling by inducing STAT1, which competes with STAT3 for binding to the IL-6 receptor, thereby inhibiting IL-6-mediated STAT3 phosphorylation.
* **IL-1 signaling:** IL-1 is a potent inflammatory cytokine that can enhance Th17 differentiation. Its signaling pathway is negatively regulated by:
* **IL-1 receptor antagonist (IL-1Ra):** IL-1Ra competes with IL-1 for binding to the IL-1 receptor, blocking IL-1 signaling.
* **IL-10:** This cytokine inhibits IL-1-induced Th17 differentiation by suppressing IL-1 production and activating STAT3, which competes with STAT1 for binding to the IL-1 receptor, thereby inhibiting IL-1 signaling.
* **Other inhibitory signals:** Other inhibitory signals, such as IL-2 and IL-21, can also suppress Th17 differentiation by activating specific signaling pathways that interfere with the differentiation program.

**2. Induction of anti-inflammatory factors:**
* **IL-10:** IL-10 is a potent anti-inflammatory cytokine that suppresses Th17 differentiation by inhibiting IL-6 and IL-23 production, as well as promoting the differentiation of regulatory T cells (Tregs), which suppress inflammatory responses.
* **TGF-β:** In the absence of pro-inflammatory signals, TGF-β can induce the differentiation of Tregs, which suppress Th17 differentiation and promote immune tolerance.
* **Other anti-inflammatory factors:** Other anti-inflammatory factors, such as IL-35 and IL-27, can also suppress Th17 differentiation by activating STAT1, which inhibits the expression of Th17-associated transcription factors.

**3. Suppression of Th17-associated transcription factors:**
* **RORγt:** Retinoic acid receptor-related orphan receptor gamma t (RORγt) is a master transcription factor that drives Th17 differentiation. Negative regulation of RORγt expression can occur through:
* **STAT1:** STAT1 can suppress RORγt expression by inhibiting the activity of the IL-6-induced STAT3 pathway.
* **FOXP3:** Forkhead box P3 (FOXP3) is a key transcription factor for Tregs. FOXP3 can directly suppress RORγt expression, thereby inhibiting Th17 differentiation.
* **Other transcription factors:** Other transcription factors involved in Th17 differentiation, such as RORα and IRF4, can also be negatively regulated by specific signaling pathways and transcription factors.

**4. Epigenetic modifications:**
* **Histone modifications:** Epigenetic modifications, such as histone acetylation and methylation, play crucial roles in regulating gene expression during Th17 differentiation. Specific enzymes, such as histone deacetylases (HDACs) and histone methyltransferases (HMTs), can modify histone tails, influencing chromatin accessibility and gene expression.
* **DNA methylation:** DNA methylation is another epigenetic modification that can influence gene expression. Methylation of DNA can inhibit gene transcription, while demethylation can activate gene expression.
* **MicroRNAs (miRNAs):** miRNAs are small non-coding RNAs that can regulate gene expression by targeting specific mRNAs for degradation or translational repression. Specific miRNAs can target mRNAs encoding key components of the Th17 differentiation program, thereby inhibiting Th17 cell development.

**5. Cellular interactions:**
* **Treg-Th17 interaction:** Tregs can suppress Th17 differentiation by producing inhibitory cytokines, such as IL-10 and TGF-β, and by directly interacting with Th17 cells through cell-cell contact.
* **Other cellular interactions:** Interactions with dendritic cells, macrophages, and other immune cells can also influence the differentiation of Th17 cells and their negative regulation.

Overall, negative regulation of T-helper 17 cell lineage commitment is a complex process involving various mechanisms that ensure a balanced immune response and prevent excessive inflammation.'
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Proteins (1)

ProteinDefinitionTaxonomy
Lysyl oxidase homolog 3A lysyl oxidase homolog 3 that is encoded in the genome of human. [PRO:DNx, UniProtKB:P58215]Homo sapiens (human)

Compounds (4)

CompoundDefinitionClassesRoles
pyrithionepyrithione : A pyridinethione that is pyridine-2(1H)-thione in which the hydrogen attached to the nitrogen is replaced by a hydroxy group. It is a Zn(2+) ionophore; the zinc salt is used as an antifungal and antibacterial agent.

pyrithione: split from cephalosporin molecule; some metal complexes of this have fumarate reductase inhibitory activity and may be useful against trypanosomes; RN given refers to parent cpd; structure
monohydroxypyridine;
pyridinethione
ionophore
aminopropionitrileAminopropionitrile: Reagent used as an intermediate in the manufacture of beta-alanine and pantothenic acid.aminopropionitrileantineoplastic agent;
antirheumatic drug;
collagen cross-linking inhibitor;
plant metabolite
disulfiramorganic disulfide;
organosulfur acaricide
angiogenesis inhibitor;
antineoplastic agent;
apoptosis inducer;
EC 1.2.1.3 [aldehyde dehydrogenase (NAD(+))] inhibitor;
EC 3.1.1.1 (carboxylesterase) inhibitor;
EC 3.1.1.8 (cholinesterase) inhibitor;
EC 5.99.1.2 (DNA topoisomerase) inhibitor;
ferroptosis inducer;
fungicide;
NF-kappaB inhibitor
thiramthiram : An organic disulfide that results from the formal oxidative dimerisation of N,N-dimethyldithiocarbamic acid. It is widely used as a fungicidal seed treatment.

Thiram: A dithiocarbamate chemical, used commercially in the rubber processing industry and as a fungicide. In vivo studies indicate that it inactivates the enzyme GLUTATHIONE REDUCTASE. It has mutagenic activity and may induce chromosomal aberrations.
organic disulfideantibacterial drug;
antifungal agrochemical;
antiseptic drug