IL-12 signaling via Stat4
IL-12 is a cytokine that promote cellular immune responses and support innate immunity, DCs that are promoted to migrate into secondary organs by inflammatory cytokines or microbial agents, as well as macrophages can secrete IL-12. This cytokine
- Induces proliferation of T cells and NK cells
- Drives the differentiation of Th1 cells
- Enhances cytotoxic activity of NK and T cells by inducing IFN-γ production.
Stat4 is the critical mediator of IL-12-stimulated gene regulation. This is supported by the similar phenotypes displayed by Stat4-deficient and IL-12- and IL-12-receptor deficient mice. Mice deficient in Stat4 have impaired Th1 cell differentiation and cell-mediated immunity. IFN-γ production and NK cell cytotoxicity in response to IL-12 is abrogated in these mice. Recently, transgenic mice were generated from Stat4 deficient mice, expressing either the alternative splice form Stat4-α or β, which lacks the C-terminal transcriptional activation domain. The phenotype of these mice demonstrates that the two isoforms have distinct roles in IL-12 induced response in T cells.
Precisely Stat4-α is required for the production of maximal IFN-γ levels; while the Stat4-β isoform is involved in mediating IL-12 induced proliferation response. Both isoforms can promote Th1 differentiation.
The activation of several IL-12-regulated genes can be mediated by both isoforms, indicating that the Stat4 transactivation domain is not always required for transcriptional activation. Probably other transcription factors act in concert with Stat4 and provide the transactivation function required for recruiting the transcription machinery.
One of the most prominent target genes induced by IL-12 via Stat4 is IFN-γ. A direct role of Stat4 in IFN-γ regulation appears likely, because binding of Stat4 to nonconsensus sites in the first intron of the human IFN-γ locus has been demonstrated.
Although IL-12 appears to be the prominent activator of Stat4, IFN-α and β can also directly activate STAT4. This is probably required to elevate IFN-γ production during viral infections.
In addition, IL-23 a newly discovered cytokine, which shares a subunit with IL-12 is an inductor of STAT4 activation and might also participate in the proliferation signal in memory T cells. The exact function of IL-23 in host defense and autoimmune disease has still to be elucidated.
Stat4-deficient mice are resistant to autoimmune diseases dependent on Th1 cells, and recent research work indicates that STAT4 is not only required for the development of Th1-type immune response via the IL-12 mediated activation pathway, but also seems to be involved in Th2-type immune response process. Data indicate that STAT4- mediated signaling is not only important in Th1 autoimmune diseases, but also play a role in the development of local allergic airway response by influencing the production of chemokines and the accumulation of effector cells important in the inflammatory response.