title: Interleukin-35 administration counteracts established murine type 1 diabetes--possible involvement of regulatory T cells.
abstract: The anti-inflammatory cytokine IL-35 is produced by regulatory T (Treg) cells to suppress autoimmune and inflammatory responses. The role of IL-35 in type 1 diabetes (T1D) remains to be answered. To elucidate this, we investigated the kinetics of Treg cell response in the multiple low dose streptozotocin induced (MLDSTZ) T1D model and measured the levels of IL-35 in human T1D patients. We found that Treg cells were increased in MLDSTZ mice. However, the Treg cells showed a decreased production of anti-inflammatory (IL-10, IL-35, TGF-β) and increased pro-inflammatory (IFN-γ, IL-2, IL-17) cytokines, indicating a phenotypic shift of Treg cells under T1D condition. IL-35 administration effectively both prevented development of, and counteracted established MLDSTZ T1D, seemingly by induction of Eos expression and IL-35 production in Treg cells, thus reversing the phenotypic shift of the Treg cells. IL-35 administration reversed established hyperglycemia in NOD mouse model of T1D. Moreover, circulating IL-35 levels were decreased in human T1D patients compared to healthy controls. These findings suggest that insufficient IL-35 levels play a pivotal role in the development of T1D and that treatment with IL-35 should be investigated in treatment of T1D and other autoimmune diseases.
authors.affiliation: Department of Medical Cell Biology, Biomedical Centre, Uppsala University, Uppsala, Sweden.
authors.forename: Kailash
authors.initials: K
authors.lastname: Singh
authors.affiliation: Department of Medical Cell Biology, Biomedical Centre, Uppsala University, Uppsala, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Kadesjö
authors.affiliation: Department of Medical Cell Biology, Biomedical Centre, Uppsala University, Uppsala, Sweden.
authors.forename: Julia
authors.initials: J
authors.lastname: Lindroos
authors.affiliation: Department of Medical Cell Biology, Biomedical Centre, Uppsala University, Uppsala, Sweden.
authors.forename: Marcus
authors.initials: M
authors.lastname: Hjort
authors.affiliation: Department of Medical Cell Biology, Biomedical Centre, Uppsala University, Uppsala, Sweden.
authors.forename: Marcus
authors.initials: M
authors.lastname: Lundberg
authors.affiliation: 1] Department of Medical Cell Biology, Biomedical Centre, Uppsala University, Uppsala, Sweden [2] Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Espes
authors.affiliation: 1] Department of Medical Cell Biology, Biomedical Centre, Uppsala University, Uppsala, Sweden [2] Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Per-Ola
authors.initials: PO
authors.lastname: Carlsson
authors.affiliation: Department of Medical Cell Biology, Biomedical Centre, Uppsala University, Uppsala, Sweden.
authors.forename: Stellan
authors.initials: S
authors.lastname: Sandler
authors.affiliation: Department of Medical Cell Biology, Biomedical Centre, Uppsala University, Uppsala, Sweden.
authors.forename: Lina
authors.initials: L
authors.lastname: Thorvaldson
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000517:prevention & control; D016753:Interleukin-10 / Q000097:blood; D007376:Interleukin-2 / Q000378:metabolism; D007378:Interleukins / Q000008:administration & dosage* / Q000097:blood / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D015778:Minor Histocompatibility Antigens; D010641:Phenotype; D018121:Receptors, Cytokine / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000096:biosynthesis / Q000302:isolation & purification; D013154:Spleen / Q000378:metabolism; D013311:Streptozocin / Q000633:toxicity; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000097:blood
chemical_list: D016207:Cytokines; C499601:Ebi3 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D007378:Interleukins; D015778:Minor Histocompatibility Antigens; D018121:Receptors, Cytokine; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C532417:interleukin-35, human; C569375:interleukin-35, mouse; D016753:Interleukin-10; D013311:Streptozocin