The Role, Involvement and Function(s) of Interleukin-35 and Interleukin-37 in Disease Pathogenesis

Abstract

The recently identified cytokines-interleukin (IL)-35 and interleukin (IL)-37-have been described for their anti-inflammatory and immune-modulating actions in numerous inflammatory diseases, auto-immune disorders, malignancies, infectious diseases and sepsis. Either cytokine has been reported to be reduced and in some cases elevated and consequently contributed towards disease pathogenesis. In view of the recent advances in utilizing cytokine profiles for the development of biological macromolecules, beneficial in the management of certain intractable immune-mediated disorders, these recently characterized cytokines (IL-35 and IL-37) offer potential as reasonable targets for the discovery of novel immune-modulating anti-inflammatory therapies. A detailed comprehension of their sophisticated regulatory mechanisms and patterns of expression may provide unique opportunities for clinical application as highly selective and target specific therapeutic agents. This review seeks to summarize the recent advancements in discerning the dynamics, mechanisms, immunoregulatory and anti-inflammatory actions of IL-35 and IL-37 as they relate to disease pathogenesis.

Keywords: cytokines; interleukin-35; interleukin-37; pathogenesis.

Figure 1

Schematic representation of immunopathology resulting from unregulated cytokine activation.

Figure 2

Schematic representation of pro-inflammatory and anti-inflammatory cytokines constituting the IL-12 cytokine family. All family members are made up of an alpha and beta sub unit (α/β) fused together via disulphide bonds. Sensu stricto, IL-12 and IL-23 represent pro-inflammatory members of this family, while IL-35 is strictly anti-inflammatory. IL-27 is pleotropic in nature. IL-39 on the other hand is relatively less characterized but accumulating evidence point at its pro-inflammatory actions [13].

Figure 3

The receptor subtypes that make up the IL-12 cytokine receptor family, comprising five receptor sub units. A propensity for receptor sharing among family members exists owing to similar α and β subunits within this cytokine family. Bipartite receptors pairs (homodimers or heterodimers are employed by IL-35 for signal transduction).

Figure 4

Schematic representation of IL-35 mediated suppression involving the subversion of T_eff cell proliferation and the induction of a potent regulatory population of IL-35 producing T_regs and B_regs that function exclusively via IL-35.

Figure 5

IL-37 processing and release. Precursor IL-37 is processed by caspase-1 to the mature form (IL-37) which subsequently translocates to the nucleus upon binding to SMAD3. The SMAD3/IL-37 complex inhibits pro-inflammatory cytokine gene transcription in the nucleus and in consort with the tripartite molecule (IL-37/IL-18Rα/IL-1R8) inhibits downstream signal transduction pathways including NF-κB and mitogen activated protein kinase (MAPK) pathway. Adapted with modifications from [77].