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.
IFNα and IFNβ Secreted by leukocytes, respectively fibroblasts, IFNα IFNβ together regulate antiviral immunity, cell proliferation and anti-tumor effects. 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. 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. Additionally, other cytokines like IL2, IL 27, IL35, IL18 and IL21 are known to activate STAT4. == Inhibitors of STAT4 signalling pathways ==