Page last updated: 2024-10-24

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.'"

Proteins (1)

ProteinDefinitionTaxonomy
Tyrosine-protein phosphatase non-receptor type 2A tyrosine-protein phosphatase non-receptor type 2 that is encoded in the genome of human. [PRO:DNx, UniProtKB:P17706]Homo sapiens (human)

Compounds (30)

CompoundDefinitionClassesRoles
5-iodo-2-(oxaloamino)benzoic acidorganoiodine compound
lithocholic acidlithocholate : A bile acid anion that is the conjugate base of lithocholic acid.

lithocholic acid : A monohydroxy-5beta-cholanic acid with a alpha-hydroxy substituent at position 3. It is a bile acid obtained from chenodeoxycholic acid by bacterial action.

Lithocholic Acid: A bile acid formed from chenodeoxycholate by bacterial action, usually conjugated with glycine or taurine. It acts as a detergent to solubilize fats for absorption and is itself absorbed. It is used as cholagogue and choleretic.
bile acid;
C24-steroid;
monohydroxy-5beta-cholanic acid
geroprotector;
human metabolite;
mouse metabolite
glycyrrhetinic acidcyclic terpene ketone;
hydroxy monocarboxylic acid;
pentacyclic triterpenoid
immunomodulator;
plant metabolite
oleanolic acidhydroxy monocarboxylic acid;
pentacyclic triterpenoid
plant metabolite
vanadatesvanadate(3-) : A vanadium oxoanion that is a trianion with formula VO4 in which the vanadium is in the +5 oxidation state and is attached to four oxygen atoms.

Vanadates: Oxyvanadium ions in various states of oxidation. They act primarily as ion transport inhibitors due to their inhibition of Na(+)-, K(+)-, and Ca(+)-ATPase transport systems. They also have insulin-like action, positive inotropic action on cardiac ventricular muscle, and other metabolic effects.
trivalent inorganic anion;
vanadium oxoanion
EC 3.1.3.1 (alkaline phosphatase) inhibitor;
EC 3.1.3.16 (phosphoprotein phosphatase) inhibitor;
EC 3.1.3.41 (4-nitrophenylphosphatase) inhibitor;
EC 3.1.3.48 (protein-tyrosine-phosphatase) inhibitor
ursolic acidhydroxy monocarboxylic acid;
pentacyclic triterpenoid
geroprotector;
plant metabolite
madecassic acidmonocarboxylic acid;
pentacyclic triterpenoid;
tetrol
antioxidant;
plant metabolite
maslinic acid(2Alpha,3beta)-2,3-dihydroxyolean-12-en-28-oic acid: from Luehea divaricata and Agrimonia eupatoriadihydroxy monocarboxylic acid;
pentacyclic triterpenoid
anti-inflammatory agent;
antineoplastic agent;
antioxidant;
plant metabolite
geniposideterpene glycoside
asiatic acidmonocarboxylic acid;
pentacyclic triterpenoid;
triol
angiogenesis modulating agent;
metabolite
celastrolmonocarboxylic acid;
pentacyclic triterpenoid
anti-inflammatory drug;
antineoplastic agent;
antioxidant;
EC 5.99.1.3 [DNA topoisomerase (ATP-hydrolysing)] inhibitor;
Hsp90 inhibitor;
metabolite
cryptotanshinonecryptotanshinone: from Salvia miltiorrhizaabietane diterpenoidanticoronaviral agent
boswellic acidboswellic acid: ursane type; RN given refers to (3alpha,4beta)-isomer; active principle of salai guggal; see also record for salai guggaltriterpenoid
procurcumenolprocurcumenol: RN given for (1S-(1alpha,3abeta,8aalpha))-isomer; epiprocurcumenol is the (1S-(1alpha,3aalpha,8aalpha))-isomer; a TNF-alpha antagonist isolated from Curcuma zedoaria; structure in first sourcesesquiterpenoid
pinocembrin
genipiniridoid monoterpenoidanti-inflammatory agent;
antioxidant;
apoptosis inhibitor;
cross-linking reagent;
hepatotoxic agent;
uncoupling protein inhibitor
2-(oxaloamino)benzoic acid(oxaloamino)benzoic acid
chlorogenic acidcaffeoylquinic acid: Antiviral Agent; structure in first source

chlorogenate : A monocarboxylic acid anion that is the conjugate base of chlorogenic acid; major species at pH 7.3.
cinnamate ester;
tannin
food component;
plant metabolite
tocopherylquinonetocopherylquinone: RN refers to (3R-(3R*,7R*,11R*))-isomer; structure
illudalic acidilludalic acid: isolated from Clitocybe illudens; structure in first source
eupatoriopicrinegermacranolide
2-amino-6-chloropurine6-chloroguanine : An organochlorine compound that is 7H-purin-2-amine substituted by a chloro group at position 6.

6-chloroguanine: an antimalarial that inhibits hypoxanthine-guanine-xanthine phosphoribosyltransferase; structure in first source
2-aminopurines;
organochlorine compound
corosolic acidtriterpenoidmetabolite
11-keto-boswellic acid
3-epioleanolic acidtriterpenoidmetabolite
oleanonic acidoleanonic acid: structure in first source
zedoarondiolzedoarondiol: structure in first source
formylchromoneformylchromone: structure in first source
rk 682
variabilinvariabilin: an RGD-containing antagonist of glycoprotein IIb-IIIa from the hard tick, Dermacentor variabilis; amino acid sequence given in first source