Figure 2. Cross-regulation of IL-12 family members and their effect on RA pathogenesis.

While IL-12, IL-23 and IL-27 are produced from antigen presenting cells, IL-35 is mostly secreted from Tregs. IL-12 and IL-27 drive differentiation of TH-1 cells and both family members suppress TH-2 and TH-17 polarization. The anti-inflammatory effects of IL-27 is also associated with production of IL-10 from Tr1 and myeloid cells as well as reducing the expression of receptors for TNF-α and IL-1β on myeloid cell and maturation of osteoclast precursors to mature osteoclasts. Presence of IL-27 prior to TH-17 development in experimental arthritis inhibits IL-17 mediated leukocyte migration, angiogenesis, bone erosion and ameliorates disease pathogenesis. Consistently, TH-17 cell differentiation is inhibited by IL-35; however, unlike IL-12 and IL-27, IL-35 is also capable of suppressing TH-1 development. The role of IL-23 on disease pathogenesis is due in part to its effect on TH-17 cell maintenance as well as its ability to activate production of IL-1β and TNF-α from myeloid cells and IL-6 from RA fibroblasts. We conclude that while IL-12, IL-27 and IL-35 display a protective role in arthritis in contrast IL-23 perpetuates arthritis pathogenesis.