Biology of recently discovered cytokines
Biology of recently discovered cytokines:
IL-27 is a recently identified heterodimeric cytokine produced in response to microbial and host derived inflammatory cues. Initial studies indicated that IL-27 promotes the generation of Th1 responses required for resistance to intracellular infection and unveiled the molecular mechanisms mediating this effect. However, subsequent work uncovered a role for IL-27 in the suppression of Th1 and Th2 responses. Thus, by discussing its pleotropic functions in the context of infection-induced immunity and by drawing parallels to fellow IL-6/IL-12 family cytokines, this review will attempt to reconcile the pro- and anti-inflammatory effects of IL-27.
The interleukin-27 receptor complex
All IL-6/IL-12 family cytokines propagate intracellular signaling through transmembrane receptor complexes that include either IL-12Rβ1 or GP130. Restricted to mature lymphoid cells, IL-12Rβ1 is a component in the heterodimeric receptors for IL-12 and IL-23. Accordingly, IL-12Rβ1 defects result in enhanced susceptibility to intracellular infection and compromised adaptive immunity. In contrast, GP130 is expressed throughout development by a range of immune and non-immune cells. Because GP130 is a component in heterodimeric receptors for several cytokines, including IL-6, IL-11, LIF (leukemia inhibitory factor), G-CSF (granulogyte colony-stimulating factor) and Oncostatin M, germline deletion of this gene leads to gross developmental defects. Therefore, due to the broad distribution of this shared receptor component, the distinct functions and tissue tropisms of GP130 associated cytokines are determined by the availability of ligand specific co-receptors .
Interleukin-27 can promote type I inflammatory responses
IL-6/IL-12 family cytokines play key roles in the generation and regulation of inflammatory responses. For instance, IL-12 promotes resistance to intracellular infection by inducing the production of IFN-γ, the signature cytokine of type I (Th1) immune responses. Though many factors coordinate the generation of type I immunity, IL-12 is a central figure; required for optimal differentiation of naïve CD4+ T cells into mature Th1 effector cells and able to induce the secretion of IFN-γ by NK cells and CD8+ T cells. Thus, based on a significant degree of sequence and structural homology, it was predicted that, like IL-12, IL-27 could promote Th1 responses. In accord with this hypothesis, recombinant IL-27 can augment proliferation and secretion of IFN-γ by naïve CD4+ T cells and when combined with IL-12, can synergize to induce IFN-γ production by human NK cells. Correspondingly, naïve WSX-1 deficient CD4+T cells produce less IFN-γ than wild-type counterparts when cultured under non-polarizing conditions. Likewise, during in vitro Th1 differentiation with IL-12 and high doses of either α T-cell receptor antibody or ConA, WSX-1-/- CD4+ T cells produce less IFN-γ than wild-type counterparts.
Journal of Cytokine Biology