title: Neutralizing Anti-IL20 Antibody Treatment Significantly Modulates Low Grade Inflammation without Affecting HbA1c in Type 2 Diabetic db/db Mice.
abstract: Low grade inflammation is present in pre-clinical and human type 2 diabetes. In this process, several cytokines like IL-1β and inflammatory cells like macrophages are activated and demonstrated to participate to the disease initiation and progression. IL-20 is a cytokine known to play non-redundant roles in progression of several inflammatory diseases. To address the therapeutic effect of inhibiting the IL-20 pathway in diabetes, diabetic db/db mice were treated with neutralizing anti-IL20 antibodies in vivo and both metabolic and inflammatory parameters were followed. Diabetic islets expressed the IL-20 cytokine and all IL-20 receptor components in elevated levels compared to resting non-diabetic islets. Islets were responsive to ex vivo IL-20 stimulation measured as SOCS induction and KC and IL-6 production. Neutralizing anti-IL20 treatment in vivo had no effect on HbA1c or weight although the slope of blood glucose increase was lowered. In contrast, anti-IL20 treatment significantly reduced the systemic low-grade inflammation and modulated the local pancreatic immunity. Significant reduction of the systemic IL-1β and MCP-1 was demonstrated upon anti-IL20 treatment which was orchestrated with a reduced RANTES, IL-16 and IL-2 but increased TIMP-1, MCP-1 and IL-6 protein expression locally in the pancreas. Interestingly, anti-IL20 treatment induced an expansion of the myeloid suppressor CD11bGr1int macrophage while reducing the number of CD8 T cells. Taken together, anti-IL20 treatment showed moderate effects on metabolic parameters, but significantly altered the low grade local and systemic inflammation. Hence, future combination therapies with anti-IL20 may provide beneficial therapeutic effects in type 2 diabetes through a reduction of inflammation.
authors.affiliation: Department of Diabetic Complications Biology, Global Research, NovoNordisk A/S, Måløv, Denmark.
authors.forename: Christopher
authors.initials: C
authors.lastname: Mayer
authors.affiliation: Department of Diabetic Complications Biology, Global Research, NovoNordisk A/S, Måløv, Denmark.
authors.forename: Regine
authors.initials: R
authors.lastname: Bergholdt
authors.affiliation: Department of Diabetic Complications Biology, Global Research, NovoNordisk A/S, Måløv, Denmark.
authors.forename: Helena
authors.initials: H
authors.lastname: Cucak
authors.affiliation: Department of Translational Pharmacology, Global Research, NovoNordisk A/S, Måløv, Denmark.
authors.forename: Bidda Charlotte
authors.initials: BC
authors.lastname: Rolin
authors.affiliation: Department of Diabetic Complications Biology, Global Research, NovoNordisk A/S, Måløv, Denmark.
authors.forename: Anette
authors.initials: A
authors.lastname: Sams
authors.affiliation: Department of Diabetic Complications Biology, Global Research, NovoNordisk A/S, Måløv, Denmark.
authors.forename: Alexander
authors.initials: A
authors.lastname: Rosendahl
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000097:blood / Q000276:immunology / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D005434:Flow Cytometry; D015870:Gene Expression; D006442:Glycated Hemoglobin / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D007378:Interleukins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D016207:Cytokines; D006442:Glycated Hemoglobin; D007378:Interleukins; D018123:Receptors, Interleukin; D011994:Recombinant Proteins; C492510:interleukin-20 receptor; C422042:interleukin 20