IL-6 is present in beta and alpha cells in human pancreatic islets: Expression is reduced in subjects with type 1 diabetes
IL-6 is a pro-inflammatory cytokine upregulated in some autoimmune diseases. The role of IL-6 in the development of type 1 diabetes (T1D) is unclear. Clinical studies are investigating whether tocilizumab (anti-IL-6 receptor) can help preserve beta cell function in patients recently diagnosed with T...
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| Published in | Clinical immunology (Orlando, Fla.) Vol. 211; p. 108320 |
|---|---|
| Main Authors | , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Elsevier Inc
01.02.2020
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| Online Access | Get full text |
| ISSN | 1521-6616 1521-7035 1521-7035 |
| DOI | 10.1016/j.clim.2019.108320 |
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| Abstract | IL-6 is a pro-inflammatory cytokine upregulated in some autoimmune diseases. The role of IL-6 in the development of type 1 diabetes (T1D) is unclear. Clinical studies are investigating whether tocilizumab (anti-IL-6 receptor) can help preserve beta cell function in patients recently diagnosed with T1D. However, in some rodent models and isolated human islets, IL-6 has been found to have a protective role for beta cells by reducing oxidative stress. Hence, we systematically investigated local tissue expression of IL-6 in human pancreas from non-diabetic, auto-antibody positive donors and donors with T1D and T2D. IL-6 was constitutively expressed by beta and alpha cells regardless of the disease state. However, expression of IL-6 was highly reduced in insulin-deficient islets of donors with T1D, and the expression was then mostly restricted to alpha cells. Our findings suggest that the implication of IL-6 in T1D pathogenesis might be more complex than previously assumed.
•IL-6 is expressed on human pancreatic beta and alpha cells.•Beta cells are the source of majority of IL-6 in pancreatic islets.•IL-6 expression is reduced in islets of donors with type 1 diabetes, particularly in insulin-deficient islets.•IL-6 is secreted by live human islet cultures and increased upon metabolic and immune stress. |
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| AbstractList | IL-6 is a pro-inflammatory cytokine upregulated in some autoimmune diseases. The role of IL-6 in the development of type 1 diabetes (T1D) is unclear. Clinical studies are investigating whether tocilizumab (anti-IL-6 receptor) can help preserve beta cell function in patients recently diagnosed with T1D. However, in some rodent models and isolated human islets, IL-6 has been found to have a protective role for beta cells by reducing oxidative stress. Hence, we systematically investigated local tissue expression of IL-6 in human pancreas from non-diabetic, auto-antibody positive donors and donors with T1D and T2D. IL-6 was constitutively expressed by beta and alpha cells regardless of the disease state. However, expression of IL-6 was highly reduced in insulin-deficient islets of donors with T1D, and the expression was then mostly restricted to alpha cells. Our findings suggest that the implication of IL-6 in T1D pathogenesis might be more complex than previously assumed.IL-6 is a pro-inflammatory cytokine upregulated in some autoimmune diseases. The role of IL-6 in the development of type 1 diabetes (T1D) is unclear. Clinical studies are investigating whether tocilizumab (anti-IL-6 receptor) can help preserve beta cell function in patients recently diagnosed with T1D. However, in some rodent models and isolated human islets, IL-6 has been found to have a protective role for beta cells by reducing oxidative stress. Hence, we systematically investigated local tissue expression of IL-6 in human pancreas from non-diabetic, auto-antibody positive donors and donors with T1D and T2D. IL-6 was constitutively expressed by beta and alpha cells regardless of the disease state. However, expression of IL-6 was highly reduced in insulin-deficient islets of donors with T1D, and the expression was then mostly restricted to alpha cells. Our findings suggest that the implication of IL-6 in T1D pathogenesis might be more complex than previously assumed. IL-6 is a pro-inflammatory cytokine upregulated in some autoimmune diseases. The role of IL-6 in the development of type 1 diabetes (T1D) is unclear. Clinical studies are investigating whether tocilizumab (anti-IL-6 receptor) can help preserve beta cell function in patients recently diagnosed with T1D. However, in some rodent models and isolated human islets, IL-6 has been found to have a protective role for beta cells by reducing oxidative stress. Hence, we systematically investigated local tissue expression of IL-6 in human pancreas from non-diabetic, auto-antibody positive donors and donors with T1D and T2D. IL-6 was constitutively expressed by beta and alpha cells regardless of the disease state. However, expression of IL-6 was highly reduced in insulin-deficient islets of donors with T1D, and the expression was then mostly restricted to alpha cells. Our findings suggest that the implication of IL-6 in T1D pathogenesis might be more complex than previously assumed. IL-6 is a pro-inflammatory cytokine upregulated in some autoimmune diseases. The role of IL-6 in the development of type 1 diabetes (T1D) is unclear. Clinical studies are investigating whether tocilizumab (anti-IL-6 receptor) can help preserve beta cell function in patients recently diagnosed with T1D. However, in some rodent models and isolated human islets, IL-6 has been found to have a protective role for beta cells by reducing oxidative stress. Hence, we systematically investigated local tissue expression of IL-6 in human pancreata from nondiabetic, auto-antibody positive donors and donors with T1D and T2D. IL-6 was constitutively expressed by beta and alpha cells regardless of the disease state. However, expression of IL-6 was highly reduced in insulin-deficient islets of donors with T1D, and the expression was then mostly restricted to alpha cells. Our findings suggest that the implication of IL-6 in T1D pathogenesis might be more complex than previously assumed. IL-6 is a pro-inflammatory cytokine upregulated in some autoimmune diseases. The role of IL-6 in the development of type 1 diabetes (T1D) is unclear. Clinical studies are investigating whether tocilizumab (anti-IL-6 receptor) can help preserve beta cell function in patients recently diagnosed with T1D. However, in some rodent models and isolated human islets, IL-6 has been found to have a protective role for beta cells by reducing oxidative stress. Hence, we systematically investigated local tissue expression of IL-6 in human pancreas from non-diabetic, auto-antibody positive donors and donors with T1D and T2D. IL-6 was constitutively expressed by beta and alpha cells regardless of the disease state. However, expression of IL-6 was highly reduced in insulin-deficient islets of donors with T1D, and the expression was then mostly restricted to alpha cells. Our findings suggest that the implication of IL-6 in T1D pathogenesis might be more complex than previously assumed. •IL-6 is expressed on human pancreatic beta and alpha cells.•Beta cells are the source of majority of IL-6 in pancreatic islets.•IL-6 expression is reduced in islets of donors with type 1 diabetes, particularly in insulin-deficient islets.•IL-6 is secreted by live human islet cultures and increased upon metabolic and immune stress. |
| ArticleNumber | 108320 |
| Author | Gonzalez, Nathaly Anquetil, Florence Quesada-Masachs, Estefania Krogvold, Lars Dahl-Jørgensen, Knut Chu, Tiffany McArdle, Sara Rajendran, Sakthi von Herrath, Matthias Graef, Madeleine |
| AuthorAffiliation | 1 La Jolla Institute for Immunology, La Jolla, CA 4 Faculty of Medicine, University of Oslo, Oslo, Norway 2 Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway 3 Faculty of Odontology, University of Oslo, Oslo, Norway |
| AuthorAffiliation_xml | – name: 1 La Jolla Institute for Immunology, La Jolla, CA – name: 4 Faculty of Medicine, University of Oslo, Oslo, Norway – name: 3 Faculty of Odontology, University of Oslo, Oslo, Norway – name: 2 Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway |
| Author_xml | – sequence: 1 givenname: Sakthi surname: Rajendran fullname: Rajendran, Sakthi organization: La Jolla Institute for Immunology, La Jolla, CA, United States of America – sequence: 2 givenname: Florence surname: Anquetil fullname: Anquetil, Florence organization: La Jolla Institute for Immunology, La Jolla, CA, United States of America – sequence: 3 givenname: Estefania surname: Quesada-Masachs fullname: Quesada-Masachs, Estefania organization: La Jolla Institute for Immunology, La Jolla, CA, United States of America – sequence: 4 givenname: Madeleine surname: Graef fullname: Graef, Madeleine organization: La Jolla Institute for Immunology, La Jolla, CA, United States of America – sequence: 5 givenname: Nathaly surname: Gonzalez fullname: Gonzalez, Nathaly organization: La Jolla Institute for Immunology, La Jolla, CA, United States of America – sequence: 6 givenname: Sara surname: McArdle fullname: McArdle, Sara organization: La Jolla Institute for Immunology, La Jolla, CA, United States of America – sequence: 7 givenname: Tiffany surname: Chu fullname: Chu, Tiffany organization: La Jolla Institute for Immunology, La Jolla, CA, United States of America – sequence: 8 givenname: Lars surname: Krogvold fullname: Krogvold, Lars organization: Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway – sequence: 9 givenname: Knut surname: Dahl-Jørgensen fullname: Dahl-Jørgensen, Knut organization: Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway – sequence: 10 givenname: Matthias surname: von Herrath fullname: von Herrath, Matthias email: matthias@lji.org organization: La Jolla Institute for Immunology, La Jolla, CA, United States of America |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 La Jolla Institute for Immunology, 9420 Athena Circle, La Jolla, 92037 S.R. designed, performed experiments, analyzed data and wrote the manuscript. F.A. designed, performed experiments and analyzed data of DiViD cases and nPOD cases (Suppl. Table 2) and revised the manuscript. E.Q.M. critically evaluated analysis done by S.R. and F.A, performed statistical analyses, designed graphs and revised the manuscript. M.G., N.G. and T.C. performed experiments and analysed data. S.M designed the macros in Qupath and helped with evaluation of analysis. L.K. and K.D.-J. collected patient materials for the DiViD study and revised the manuscript. M.G.v.H. conceived, designed the study, interpreted data and wrote the manuscript. M.G.v.H. is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. F.A. is currently affiliated with the Novo Nordisk Diabetes Research & Development Center, Seattle, WA. Author contributions |
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