IL-35 is a novel responsive anti-inflammatory cytokine--a new system of categorizing anti-inflammatory cytokines

• Published in: PloS one 2012-03, Vol.7 (3), p.e33628-e33628
• Main Authors: Li, Xinyuan, Mai, Jietang, Virtue, Anthony, Yin, Ying, Gong, Ren, Sha, Xiaojin, Gutchigian, Stefanie, Frisch, Andrew, Hodge, Imani, Jiang, Xiaohua, Wang, Hong, Yang, Xiao-Feng
• Format: Article
• Language: English
• Subjects: Alternative Splicing; Analysis; Animals; Anti-inflammatory agents; Arthritis; Autoimmune diseases; Base Sequence; Biology; Bone morphogenetic proteins; Confidence intervals; Cytokines; Cytokines - classification; Cytokines - genetics; Cytokines - immunology; DNA Methylation; Gastroenterology; Gene Expression; Genomes; Human tissues; Humans; Immune Tolerance - immunology; Immunosuppression; Immunotherapy; Inflammation; Inflammation - immunology; Inflammation - prevention & control; Inflammatory bowel disease; Interleukin; Interleukin 10; Interleukins; Interleukins - biosynthesis; Interleukins - chemistry; Interleukins - genetics; Interleukins - immunology; Lymphocytes; Medicine; Mice; Mice, Knockout; MicroRNA; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Models, Immunological; Promoter Regions, Genetic; Protein binding; Protein Subunits; Proteins; Regulatory mechanisms (biology); RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Standard deviation; Statistical analysis; Statistical methods; T-Lymphocytes, Regulatory - immunology; Tissues; Transcription factors; Transforming growth factor; Transforming Growth Factor beta - immunology; Transforming growth factors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0033628

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.