Map Key
Generic Enzyme
Generic kinase
Protein kinase
Lipid kinase
Generic phosphatase
Protein phosphatase
Lipid phosphatase
Generic phospholipase
Generic protease
Metalloprotease
G-alpha
RAS - superfamily
G beta/gamma
Regulators (GDI, GAP, GEF)
Generic channel
Ligand-gated channel
Voltage-gated channel
Transporter
Normal process
Pathological process
Positive effect
Negative effect
Unspecified effect
Technical link
Disrupts in disease
Emerges in disease
Enhances in disease
Weakens in disease
Organsim specific interaction

Generic binding protein
Receptor ligand
Cell membrane glycoprotein
Transcription factor
DNA
RNA
Compound
Inorganic ion
Predicted metabolite or user's structure
Reaction
Generic receptor
GPCR
Receptors with enzyme activity
Mitochondria
EPR
Golgi
Nucleus
Lysosome
Peroxisome
Cytoplasm
Extracellular

Normal process
Pathological process
Binding
Cleavage
Covalent modifications
Phosphorylation
Dephosphorylation
Transformation
Transport
Catalysis
Transcription regulation
MicroRNA binding
Competition
Influence on expression
Unspecified interactions
Pharmacological effect
Toxic effect
Group relation
Complex subunit
Similarity reaction
A complex or a group
Organism specific object

Immune response IL-12 signaling pathway


Log In to Post A Comment

Immune response IL-12 signaling pathway

IL-12 signaling pathway

Interleukin-12 ( IL-12 ) is a key immunoregulatory cytokine that coordinatesinnate and adaptive immune responses. Major event of IL-12 signaling is activationof Signal transducers and activators of transcription ( STAT s), mainlySTAT4, to promote differentiation of native CD4+T cells into T-helper (Th) 1cells, NK cellular cytotoxicity and proliferation of T cells [1].

The main role of IL-12 is activation of Interferon gamma ( IFN-gamma )production. Upon binding to its receptor, IL-12 activates Janus family kinasesTyrosine kinase 2 ( Tyk2 ) and Janus kinase 2 ( Jak2 ). I nterleukin 12receptor, beta 1 ( IL-12RBl ) binds the Tyk2, whereas I nterleukin 12receptor, beta 2 ( IL-12RB2 ) associates with Jak2. Jak2phosphorylates the tyrosine residues of STAT3 and STAT4. They translocateto the nucleus and bind to the promoter site of IFN-gamma. STAT4 also recruits Junoncogene ( c-Jun ) to IFN-gamma promoter [2], [3],[4].

Upon IL-12 action, STAT4 also induces transcription of IL-12RB2and Interleukin 18 receptor 1 ( IL-18RB1 ), that leads to amplification ofIL-12 signaling and Th1 cells differentiation [5], [6],[7], [8], [9]. Also, IL-12 promotesexpression of Interferon regulatory factor 1 ( IRF1 ) and 4 ( IRF4 ) in aSTAT4 -dependent manner [10], [11].

In addition, IL-12 promotes expression of Interleukin 2 receptor, alpha (IL-2R ) by recruiting STAT4 and c-Jun to the promoter ofIL-2R and thereby enhancing T cell proliferation [12], [13].

In NK cells, IL-12 induce d cytotoxic events by STAT4 activation ofPerforin 1 ( perforin ) gene at its promoter [14].

And lastly, IL-12 -induce d STAT4 activation leading to expression ofGCNT1 glucosaminyl (N-acetyl) transferase 1 core 2 ( G6NT ), enzyme responsiblefor SELP selectin P (P-selectin ) ligand formation. This augments cell adhesionduring T-cell differentiation [15], [16], [17],[18].

IL-12 has the capacity to induce STAT5 protein. JAK2 activationby IL-12R induces STAT5 phosphorylation thus promoting cellularproliferation [19]. However, there is evidence that STAT5A can suppressIL-12 -induced Th1 cell differentiation through the induction of Suppressor ofcytokine signaling 3 ( SOCS3 ) expression. SOCS3 inhibits IL-12signaling by binding to the STAT4 docking site of the IL-12RB2 subunit[20], [21].

Another negative regulator of IL-12 signaling is Protein inhibitor of activatedSTAT 2 ( PIAS2 ). It binds to STAT4 and represses its transcriptionalactivity [22].

It was shown that STAT4 undergoes proteosomal degradation during IL-12signaling. PDZ and LIM domain 2 ( PDLIM2 ) was identified as an ubiquitin E3ligase that acts on STAT4 protein to cause its proteosome-mediated degradation[23], [24].