IL-35 Is a Novel Responsive Anti-inflammatory Cytokine — A New System of Categorizing Anti-inflammatory Cytokines

It remains unknown whether newly identified anti-inflammatory/immunosuppressive cytokine interleukin-35 (IL-35) is different from other anti-inflammatory cytokines such as IL-10 and transforming growth factor (TGF)-β in terms of inhibition of inflammation initiation and suppression of full-blown inflammation. Using experimental database mining and statistical analysis methods we developed, we examined the tissue expression profiles and regulatory mechanisms of IL-35 in comparison to other anti-inflammatory cytokines. Our results suggest that in contrast to TGF-β, IL-35 is not constitutively expressed in human tissues but it is inducible in response to inflammatory stimuli. We also provide structural evidence that AU-rich element (ARE) binding proteins and microRNAs target IL-35 subunit transcripts, by which IL-35 may achieve non-constitutive expression status. Furthermore, we propose a new system to categorize anti-inflammatory cytokines into two groups: (1) the house-keeping cytokines, such as TGF-β, inhibit the initiation of inflammation whereas (2) the responsive cytokines including IL-35 suppress inflammation in full-blown stage. Our in-depth analyses of molecular events that regulate the production of IL-35 as well as the new categorization system of anti-inflammatory cytokines are important for the design of new strategies of immune therapies

A new working model of responsive anti-inflammatory cytokine and housekeeping cytokine.

<p>Homeostatic tissues express “house-keeping” anti-inflammatory cytokines TGF-β1, TGF-β2, TGF-β3 to prevent it from initiation of inflammation. When tissues get inflamed, proinflammatory factors may stimulate tissues to express “responsive” anti-inflammatory cytokines such as IL-35 by specific transcription factors to counteract inflammation response. Furthermore, ARE binding proteins and MicroRNAs are responsible of the quick degradation of IL-35 mRNA afterwards, by which IL-35 achieve non-constitutive expression status in tissues again.</p

3′-untranslated region in mRNA of anti-inflammatory cytokines in human contain signals for RNA protein binding.

<p>3′-untranslated region in mRNA of anti-inflammatory cytokines in human contain signals for RNA protein binding.</p

Higher hypomethylation status is positively associated with higher expression of IL-35 gene.

<p>A. Concentrations of SAM and SAH in mouse tissues were previously examined by Ueland et al. B. Correlation of suppressive cytokines and TGF-β receptors with SAM/SAH ratios in mouse tissues. C. Schematic presentation of how IL-35 may be regulated by methylation status. S-Adenosylhomocysteine (SAH) and S-Adenosylmethionine (SAM) are intermediate metabolites of homocysteine-methionine metabolism cycle. SAH is a potent inhibitor of cellular methylation. High SAM/SAH ratio is associated with hypermethylation of DNA and no IL12A/Ebi3 expression. Low SAM/SAH ratio is associated with hypomethylation of DNA and Ebi3 can be expressed.</p

Differential response of IL-35 subunits, IL-10, and TGF-β1 in response to proinflammatory cytokine IL-1β.

<p>Differential response of IL-35 subunits, IL-10, and TGF-β1 in response to proinflammatory cytokine IL-1β.</p

IL-35 subunit mRNAs have been shown to be induced by stimulation in various human cell types.

<p>IL-35 subunit mRNAs have been shown to be induced by stimulation in various human cell types.</p

Alternative promoter and alternative splicing regulate the expression and structures of anti-inflammatory cytokines.

<p>Alternative promoter and alternative splicing regulate the expression and structures of anti-inflammatory cytokines.</p