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.
Highlights
Under the circumstances of host pathology and defense, the cells comprising the immune system produce an assortment of biological products that enable them to communicate and mount specific and effective immune responses
Suffice to say that Tregs being a primary source of IL-35, such decrease translates to a corresponding decrease in peripheral circulating levels of IL-35 invariably offsetting an imbalance in the mitigating counter-inflammatory response required to effectively curb mucosal release of inflammatory mediators exacerbating symptoms in patients with irritable bowel disease (IBD) [46]
Hu et al [92] illustrated a reduction in IL-37 mRNA and a concomitant increase in the levels of IL-1β, IL-6 as well as TNF-α in LPS-stimulated sputum taken from asthmatic patients, the inflammatory cytokine expression observed was potently antagonized by co-incubation with IL-37 [92]
Summary
Under the circumstances of host pathology and defense, the cells comprising the immune system produce an assortment of biological products that enable them to communicate and mount specific and effective immune responses. The ensuing novel heterodimer formed (Ebi3/p35) was later discovered to be capable of exerting potent immunoregulatory actions [16,17] Both α and β-subunits of IL-35 are largely derived from regulatory Foxp3+ Tregs distinctive from most IL-12 cytokine family members which are expressed on the surface of activated dendritic cells, B-cells, monocytes and macrophages viz antigen presenting cells via which they drive TH1 responses solely or synergistically in addition to promoting interferon-γ (IFN-γ) generation by T cells [16,18]. The suppressive capacity of Treg cells in (IL-35 deficient) p35−/− or Ebi3−/− murine subjects (achieved via targeted deletion of either of the two genes) is significantly reduced in contrast to their wild-type counterparts [24]
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