IL‐35 is a Novel Responsive Anti‐inflammatory Cytokine ‐ A New System of Categorizing Anti‐inflammatory Cytokines

Abstract

Interleukin‐35 (IL‐35), a recently discovered heterodimeric cytokine with anti‐inflammatory/immunosuppressive properties, has a central role in limiting the immune response in various disease models including colitis, arthritis and asthma. However, it remains unknown whether 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 or suppression of full‐blown inflammation. In this study, 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 is inducible in response to inflammatory stimuli. We also provide structural evidence suggesting that AU‐rich element (ARE) binding proteins and microRNAs target IL‐35 subunit transcripts, which are responsible for quick degradation of IL‐35. Furthermore, we propose a new system to categorize anti‐inflammatory cytokines into two groups: (1) the housekeeping 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 analysis of molecular events that regulate the production of IL‐35 and new categorization system of anti‐inflammatory cytokines are important for the design of new strategies of immune intervention. This work was partially supported by the National Institutes of Health Grants HL094451 and HL108910 (XFY), HL67033, HL82774 and HL77288 (HW).