STAT4

Signal transducer and activator of transcription 4 (STAT4) is a

Distribution of STAT4 is restricted to myeloid cells, thymus and testis.^[5] In resting human T cells it is expressed at very low levels, but its production is amplified by PHA stimulation.^[8]

Cytokines activating STAT4

IL-12

Pro-inflammatory cytokine IL-12 is produced in heterodimer form by B cells and antigen-presenting cells. Binding of IL-12 to IL-12R, which is composed of two different subunits (IL12Rβ1 and IL12Rβ2), leads to the interaction of IL12Rβ1 and IL12Rβ2 with JAK2 and TYK2, which is followed by phosphorylation of STAT4 tyrosine 693. The pathway then induces IFNγ production and Th1 differentiation. STAT4 is critical in promotion of antiviral response of natural killer (NK) cell by targeting of promotor regions of Runx1 and Runx3.^[13]

IFNα and IFNβ

Secreted by leukocytes, respectively fibroblasts, IFNα IFNβ together regulate antiviral immunity, cell proliferation and anti-tumor effects.^[14] In viral infection signalling pathway, either of IFNα or β binds to IFN receptor (IFNAR), composed of IFNAR1 and IFNAR2, immediately followed by the phosphorylation of STAT1, STAT4 and IFN target genes.^[15] During the initial phase of viral infection in NK cells, STAT1 activation is replaced by the activation of STAT4.

IL-23

Monocytes, activated dendritic cells (DC) and macrophages stimulate the accumulation of IL-23 after exposure to molecules of Gram-positive/negative bacteria or viruses. Receptor for IL-23 contains IL12β₁ and IL23R subunits, which upon binding of IL-23 promotes the phosphorylation STAT4. The presence of IL12β₁ enables similar, although weaker downstream activity as compared to IL-12. During chronic inflammation, IL-23/STAT4 signalling pathway is involved in the induction of differentiation and expansion of Th17 pro-inflammatory T helper cells.^[16]

Additionally, other cytokines like IL2, IL 27, IL35, IL18 and IL21 are known to activate STAT4.

Inhibitors of STAT4 signalling pathways

In cells with progressively increasing expression of IL12 and IL6, SOCSs production and activity suppress cytokine signalling and phosphorylation of JAK-STAT pathways in a negative feedback loop.^[17]

Other suppressors of the pathways are: protein inhibitor of activated STAT (PAIS) (regulation of transcriptional activity in the nucleus, observed in STAT4-DNA binding complex), protein tyrosine phosphatase (PTP) (removal of phosphate groups from phosphorylated tyrosine in JAK/STAT pathway proteins), STAT-interacting LIM protein (SLIM) (STAT ubiquitin E3 ligase blocking the phosphorylation of STAT4) or microRNA (miRNA) (degradation of STAT4 mRNA and its post-transcriptional regulation).^[11]

Target genes

STAT4 binds to hundreds of sites in the genome,

STAT4 is involved in several autoimmune and cancer diseases in animal models humans, significantly in the disease progression and pathology. STAT4 were significantly increased in patients with colitis ulcerative^[19] and skin T cells of psoriatic patients.^[20] Moreover, STAT4 -/- mice developed less severe experimental autoimmune encephalo-myelitis (EAE) than the wild type mice.^[21][22]

Intronic