Figure 2
From: IL-10 production by CD4+ effector T cells: a mechanism for self-regulation
Extracellular signals and intracellular pathways regulating expression of interleukin (IL)-10 gene in Th1 and Th17 cells. (a) The diagram depicts four different mechanisms of IL-10 induction in Th1 cells proposed in the literature and discussed in this review. Although not mutually exclusive, they together reveal the involvement of extracellular factors such as antigen (Ag) concentration, the cytokines IL-12 and IL-27, as well as expression of Notch and inducible costimulatory molecule (ICOS) ligands on dendritic cells (DCs). In each mechanism, distinct signal transducers and activators of transcription (STAT) proteins and/or intracellular signaling cascades have been implicated, suggesting that IL-10 expression in Th1 cells may be achieved through multiple non-redundant pathways. Nevertheless, in each case our incomplete understanding of the downstream DNA-binding regulatory elements that determine IL-10 gene activation (as indicated with question marks) leaves open the possibility for an as yet undefined unifying mechanism. (b) In Th17 cells expression of IL-10 can be induced by IL-6, IL-21, and IL-27, all of which signal through STAT3. Interestingly, IL-6 and IL-21 are known to promote Th17 differentiation, whereas IL-27 inhibits the development of Th17 cells. Although STAT3 may have a critical role, it is not yet clear whether additional signaling pathways known to be activated by each of three cytokines contribute to conditional IL-10 expression. Nevertheless, the transcriptional factor c-maf, which binds to the MARE sequence in the IL-10 promoter, seems to be a common component in all three pathways, suggesting a consensus mechanism of IL-10 expression in Th17 effectors that is currently lacking for Th1 lymphocytes (see a above).
