Biology of recently discovered cytokines: discerning the pro- and anti-inflammatory properties of interleukin-27

Abstract

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.

Figure 1

IL-27 and the IL-27 receptor complex. Heterodimeric IL-27 is the association between a helical protein, IL-27p28, and a soluble cytokine receptor-like component, EBI3. Through engagement of its cognate receptor, (IL-27R: GP130/WSX-1), IL-27 can activate a heterogeneous Jak/STAT signaling cascade. In order to emphasize structural similarities, IL-27 is depicted with fellow IL-6/IL-12 family cytokines and the conserved WSXWS motif is represented by a dark band within cytokine binding domains. To indicate functional parallels, the relative ability to activate STAT transcription factors is reflected by differences in font size. However, in this figure, the physical size of cytokine/receptor pairings or their components does not have physiological relevance. IL, interleukin; Jak, Janus kinase; STAT, signal transducer and activator of transcription.

Figure 2

The paradoxical pro- and anti-inflammatory properties of IL-27. Through ligation of its cognate receptor, IL-27 influences a range of immune cell lineages. This figure summarizes the effects of IL-27 treatment or IL-27 receptor deficiency on mast cells, monocytes, NK cells, NK T cells, CD4⁺ T cells and CD8⁺ T cells. References are listed as bracketed citations in the far right column of the figure. IFN, interferon; IL, interleukin; NK, natural killer; TNF, tumor necrosis factor.

Figure 3

Analysis of infection-induced immune responses in IL-27 receptor deficient mice. The availability of receptor deficient mice has allowed researchers to explore the role of IL-27 in vivo. This figure summarizes the immune response of WSX-1 -/- mice upon challenge with various prokaryotic and eukaryotic pathogens. References are listed as bracketed citations in the far right column of the figure. BCG, bacille Calmette-Guérin; IFN, interferon; IL, interleukin, TNF, tumor necrosis factor.