For over a decade, IL-12 has been recognized as the canonical cytokine that links innate and adaptive immunity, and with the discovery of IL-23 and IL-27 as cytokines related to IL-12, there has been a concerted effort to understand the relationship between these cytokines. Recent studies have provided new insights into the developmental pathways that promote the differentiation and function of CD4+ T helper cells and offer a dramatically altered perspective on the cause and prevention of autoimmune disease. Besides cell-cell contacts that provide activation signals via peptide-MHC/TCR and classical costimulatory interactions (B7/CD28), antigen-presenting cells communicate with T cells via cytokine production. As a consequence of interacting with various microbial products, antigen-presenting DCs and monocytes/macrophages, as well as other cell types, produce a variety of these soluble factors that are responsible for the expansion and differentiation of naive T cells to generate mature phenotypes such as Thl and Th2 cells. IL-12, discovered in 1989, is well known as a central player in promoting the differentiation of naive CD4+ T cells into mature Thl effector cells and is a potent stimulus for NK cells and CD8+ T cells to produce IFNγ.
All cytokines of the IL-12 family are produced by activated DCs and macrophages, which function as antigen-presenting cells. ex
Recently, IL-23 has been demonstrated to play a key role in the development of several autoimmune diseases such as multiple sclerosis (MS) and experimental autoimmune encephalitis (EAE). Oppmann et al. demonstrated that the IL-23pl9 subunit, a four-a helix cytokine with an overall sequence identity of approximately 40% to IL-12p35, has no biological activity by itself, but binds to IL-12p40 to form IL-23, with biological activities similar as well as distinct from IL- 12. IL-23 induces proliferation of mouse memory T cells, but IL-12 does not. IL-23 has biological functions that are similar to IL-12, such as IFNγ production from CD4 T cells, antitumor and antimetastatic activity. Similar to IL-12, IL-23 induces IFNγ production in phytohemagglutinin (PHA)-stimulated T cells. Some earlier reports also suggest that IL-23 induces a more robust and sustained cytotoxic T lymphocyte and Thl immune response than IL-12. Furthermore, IL-23N220L, an N-glycosylation mutant of this protein that shows reduced ex
In 2002, a new heterodimeric cytokine termed IL-27 that consists of Epstein-Barr virus-induced gene 3 (EBI3) and p28 was discovered. IL-27EBI3, a 33-34 kDa glycosylated protein is related to the IL-12p40 subunit of IL-12 and IL-27p28 is related to the IL-12p35 polypeptide. IL-27 is involved in early Thl initiation and possesses anti-inflammatory properties. IL-27 may also play a role in the induction of T-bet ex
By comparison to IL-12 and IL-23, which share a similar structural makeup, IL- 27 differs in that its subunits are not linked by a disulfide bond. The absence of the disulfide bond theoretically allows for production of the two subunits by distinct cells followed by extracellular association. IL-27 has attracted considerable interest as an anticancer agent due to its similarities with IL-12. IL-12 is thought to be effective against tumors because it promotes Thl polarization and, thereby, promotes cellular immune responses and proliferation of cytotoxic T lymphocytes (CTL). IL-27 enhancement of CTL activity strengthens the case that IL-27 could be a potent antitumor agent. Over ex