Type I Cytokine Family Members

In addition to the structural relationship between IL-6, IL-12, IL-23 and IL-27, all these cytokines are also produced in response to microbial and host immune stimuli, such as Toll-like receptors and IFNs. Also, Il-12p35, IL-23p19 and Il-27p28 are poorly secreted unless co-expressed with their respective partners (IL-12p40 for IL-12p35 and IL-23p19 and EBI3 for IL-27). A probably reason for the tightly regulated secretion of these proteins is that aberrant expression can result in severe inflammation.

Another common feature of type-I cytokine family members is that they activate similar JAK-STAT signalling pathways, a property that explains some of the overlapping effects on T cells.

Although Type I cytokines have been characterized on the basis of their pro-inflammatory effects, it is becoming clear that several of these proteins also have immunosuppressive properties. For example, despite a role for IL-27 in the development of TH1 cell responses there is evidence that this immune factor can also antagonize effector T cell responses.

IL6

IL-6 along with TNFα promotes innate immunity and elimination of pathogens. Il-6 was first identified as a T cell-derived cytokine that induces the maturation of B cells into antibody-producing plasma cells. IL-6 also induces hematopoiesis from stem cells and acute phase reactions by hepatocytes.

IL-6 is actually a pro-inflammatory cytokine. It is elevated in rheumatoid arthristis patients. Symptoms that accompany autoimmune disease such as fatigue, anemia, anorexia, fever and a rise in erythrocyte sedimentation rate can almost all be explained by explained by excessive IL-6 production. IL-6 also drives acute-phase proteins, including C-reactive protein and fibrinogen involved in inflammation. IL-6 also stimulates T-helper 17 cells, a newly discovered type of T cell that, by secreting IL-17 encourages activated cells to infiltrate peripheral tissues.

The IL-6 receptor complex consists of an IL-6-specific receptor chain (IL-6R) and the gp130 chain that is charged with several other cytokines.

IL-6 gene transcription is induced in cells infected by HIV.

IL-12

IL-23: has the same p40 subunit as IL-12, and this is coupled to a unique second chain, p19. Similarly the receptor for IL-23 consists of an IL-12Rβ1 subunit, in a complex with a newly identified member of the meopoietin receptor family. As expected, IL-12 and IL23 have similar functions, including the stimulation of IFNy production.

IL-27:  IL-27 is homologous to IL-12. The IL-27 receptor is also present at the surface of CD4+ T cells. Signalling through the IL-27 receptor can activate STAT1 and thereby promote expression of T-BET, a transciption factor, the target genes of which include genes encoding signature components of TH1 cells responses, IL-12Rbeta2 and IFN-gamma. IL-27 is comprised of p28, a polypeptide related to IL-12 p35, and EBI3 (Epstein-Barr virus-induced gene 3), and IL-12/IL23 p40 related protein. It beinds to a heterodimeric receptor complex formed by TCCR/WSX-1 and gp130, a common receptor subunit shared by IL-6 family cytokines. Upon secretion by activated antigen-resenting cells, IL-27 promotes the expansion of naive CD4_ T cells and drives Th1 differentation by inducing the expression of the Th1 specific transcription factor, T-bet. At the same time, Il-27 in the absence of IL-4 inhibits the expression of the Th2 specific transcription factor, GATA-3, and suppresses Th2 cytokine production. Despite its role in promoting Th1 differentiation, studies also suggest that it can prevent excessive T cell activity.