Interleukin-1 stimulates beta-cell necrosis and release of the immunological adjuvant HMGB1.
There are at least two phases of beta-cell death during the development of autoimmune diabetes: an initiation event that results in the release of beta-cell-specific antigens, and a second, antigen-driven event in which beta-cell death is mediated by the actions of T lymphocytes. In this report, the...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2006-02-01
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| Series: | PLoS Medicine |
| Online Access: | http://europepmc.org/articles/PMC1316065?pdf=render |
| _version_ | 1818700575504596992 |
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| author | Sarah A Steer Anna L Scarim Kari T Chambers John A Corbett |
| author_facet | Sarah A Steer Anna L Scarim Kari T Chambers John A Corbett |
| author_sort | Sarah A Steer |
| collection | DOAJ |
| description | There are at least two phases of beta-cell death during the development of autoimmune diabetes: an initiation event that results in the release of beta-cell-specific antigens, and a second, antigen-driven event in which beta-cell death is mediated by the actions of T lymphocytes. In this report, the mechanisms by which the macrophage-derived cytokine interleukin (IL)-1 induces beta-cell death are examined. IL-1, known to inhibit glucose-induced insulin secretion by stimulating inducible nitric oxide synthase expression and increased production of nitric oxide by beta-cells, also induces beta-cell death.To ascertain the mechanisms of cell death, the effects of IL-1 and known activators of apoptosis on beta-cell viability were examined. While IL-1 stimulates beta-cell DNA damage, this cytokine fails to activate caspase-3 or to induce phosphatidylserine (PS) externalization; however, apoptosis inducers activate caspase-3 and the externalization of PS on beta-cells. In contrast, IL-1 stimulates the release of the immunological adjuvant high mobility group box 1 protein (HMGB1; a biochemical maker of necrosis) in a nitric oxide-dependent manner, while apoptosis inducers fail to stimulate HMGB1 release. The release of HMGB1 by beta-cells treated with IL-1 is not sensitive to caspase-3 inhibition, while inhibition of this caspase attenuates beta-cell death in response to known inducers of apoptosis.These findings indicate that IL-1 induces beta-cell necrosis and support the hypothesis that macrophage-derived cytokines may participate in the initial stages of diabetes development by inducing beta-cell death by a mechanism that promotes antigen release (necrosis) and islet inflammation (HMGB1 release). |
| first_indexed | 2024-12-17T15:07:08Z |
| format | Article |
| id | doaj.art-a642320409224bc598e9f26337ad8032 |
| institution | Directory Open Access Journal |
| issn | 1549-1277 1549-1676 |
| language | English |
| last_indexed | 2024-12-17T15:07:08Z |
| publishDate | 2006-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Medicine |
| spelling | doaj.art-a642320409224bc598e9f26337ad80322022-12-21T21:43:46ZengPublic Library of Science (PLoS)PLoS Medicine1549-12771549-16762006-02-0132e1710.1371/journal.pmed.0030017Interleukin-1 stimulates beta-cell necrosis and release of the immunological adjuvant HMGB1.Sarah A SteerAnna L ScarimKari T ChambersJohn A CorbettThere are at least two phases of beta-cell death during the development of autoimmune diabetes: an initiation event that results in the release of beta-cell-specific antigens, and a second, antigen-driven event in which beta-cell death is mediated by the actions of T lymphocytes. In this report, the mechanisms by which the macrophage-derived cytokine interleukin (IL)-1 induces beta-cell death are examined. IL-1, known to inhibit glucose-induced insulin secretion by stimulating inducible nitric oxide synthase expression and increased production of nitric oxide by beta-cells, also induces beta-cell death.To ascertain the mechanisms of cell death, the effects of IL-1 and known activators of apoptosis on beta-cell viability were examined. While IL-1 stimulates beta-cell DNA damage, this cytokine fails to activate caspase-3 or to induce phosphatidylserine (PS) externalization; however, apoptosis inducers activate caspase-3 and the externalization of PS on beta-cells. In contrast, IL-1 stimulates the release of the immunological adjuvant high mobility group box 1 protein (HMGB1; a biochemical maker of necrosis) in a nitric oxide-dependent manner, while apoptosis inducers fail to stimulate HMGB1 release. The release of HMGB1 by beta-cells treated with IL-1 is not sensitive to caspase-3 inhibition, while inhibition of this caspase attenuates beta-cell death in response to known inducers of apoptosis.These findings indicate that IL-1 induces beta-cell necrosis and support the hypothesis that macrophage-derived cytokines may participate in the initial stages of diabetes development by inducing beta-cell death by a mechanism that promotes antigen release (necrosis) and islet inflammation (HMGB1 release).http://europepmc.org/articles/PMC1316065?pdf=render |
| spellingShingle | Sarah A Steer Anna L Scarim Kari T Chambers John A Corbett Interleukin-1 stimulates beta-cell necrosis and release of the immunological adjuvant HMGB1. PLoS Medicine |
| title | Interleukin-1 stimulates beta-cell necrosis and release of the immunological adjuvant HMGB1. |
| title_full | Interleukin-1 stimulates beta-cell necrosis and release of the immunological adjuvant HMGB1. |
| title_fullStr | Interleukin-1 stimulates beta-cell necrosis and release of the immunological adjuvant HMGB1. |
| title_full_unstemmed | Interleukin-1 stimulates beta-cell necrosis and release of the immunological adjuvant HMGB1. |
| title_short | Interleukin-1 stimulates beta-cell necrosis and release of the immunological adjuvant HMGB1. |
| title_sort | interleukin 1 stimulates beta cell necrosis and release of the immunological adjuvant hmgb1 |
| url | http://europepmc.org/articles/PMC1316065?pdf=render |
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