 |
 |
Interleukin-12 (IL-12) promotes cell-mediated immunity by inducing Th1 cell differentiation and activation of both T cells and NK cells. Dendritic cells and macrophages in peripheral tissues act as antigen presenting cells and secrete IL-12 as one component of the antigen response, Th1 differentiation. The role of IL-12 in cellular immunity is largely mediated by the STAT-4 transcription factor. STAT-4 is essential for IL-12 activity and the phenotype of mice lacking STAT-4 is very similar to the phenotype of mice lacking the IL-12 receptor or IL-12. The role of IL-12 in Th1 differentiation may not be to induce the Th1 cell fate, but to stimulate growth of cells determined for the Th1 cell fate by the T-bet transcription factor. Several signaling pathways contribute to IL-12 activation of STAT-4 to regulate cell-mediated immune responses. The JAK kinases such as JAK2 and TYK2 interact with the activated IL-12 receptor and tyrosine phosphorylate the IL-12 receptor and STAT-4. IL-12 also activates a map kinase pathway activating the map kinase kinase MKK6 and p38. Phosphorylation of STAT-4 on serine 721 by p38 contributes to the full transcriptional activation of genes by STAT-4. Some of the events downstream of IL-12 appear to include genes activated indirectly by STAT-4, such as genes activated by the transcription factor ERM. ERM is in the Ets family of transcription factors, is activated by IL-12 and activates IL-12 inducible genes such as Interferon-gamma that are not activated by STAT-4 itself. Interferon-gamma transcription in T cells is also activated by other signals such as from the T cell receptor. Other proteins activated transcriptionally downstream of IL-12 and STAT-4 include the chemokine receptor CCR5 and IL-18 and its receptor. Some viruses, including HIV, repress cell-mediated immunity by blocking IL-12 signaling. |
|
|
 |
|
Glenn Croston, PhD |
|
|
 |
|
|
|
|
 |
|
Kaplan, M.H., Sun, Y.L., Hoey, T., Grusby,M.J. (1996) Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice. Nature 382(6587), 174-7
Mullen, A.C., et al. (2001) Role of T-bet in commitment of TH1 cells before IL-12-dependent selection. Science 292(5523), 1907-10
Ouyang, W. et al. (1999) The Ets transcription factor ERM is Th1-specific and induced by IL-12 through a Stat4-dependent pathway. Proc Natl Acad Sci U S A 96(7), 3888-93
Thierfelder, W.E. et al. (1996) Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature 382(6587), 171-4
Visconti, R. et al. (2000) Importance of the MKK6/p38 pathway for interleukin-12-induced STAT4 serine phosphorylation and transcriptional activity. Blood 96(5), 1844-52
|
|
|
|
