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Roles of Bcl-3 in the Pathogenesis of Murine Type 1 Diabetes
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| Zeitschriftentitel: | Diabetes |
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| Personen und Körperschaften: | , , , , |
| In: | Diabetes, 59, 2010, 10, S. 2549-2557 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Diabetes Association
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| Schlagwörter: |
| Zusammenfassung: | <jats:sec><jats:title>OBJECTIVE</jats:title><jats:p>It has long been recognized that autoimmunity is often associated with immunodeficiency. The mechanism underlying this paradox is not well understood. Bcl-3 (B-cell lymphoma 3) is an atypical member of the IκB (inhibitor of the nuclear factor-κB) family that is required for lymphoid organogenesis and germinal center responses. Mice deficient in Bcl-3 are immunodeficient because of the microarchitectural defects of their lymphoid organs. The goal of this study is to define the potential roles of Bcl-3 in type 1 diabetes.</jats:p></jats:sec><jats:sec><jats:title>RESEARCH DESIGN AND METHODS</jats:title><jats:p>Bcl-3–deficient NOD mice were generated by backcrossing Bcl-3–deficient C57BL/6 mice to NOD mice. Spontaneous and induced type 1 diabetes were studied in these mice by both pathologic and immunologic means. The effect of Bcl-3 on inflammatory gene transcription was evaluated in a promoter reporter assay.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>We found that Bcl-3–deficient NOD and C57BL/6 mice were, paradoxically, more susceptible to autoimmune diabetes than wild-type mice. The increase in diabetes susceptibility was caused by Bcl-3 deficiency in hematopoietic cells but not nonhematopoietic cells. Bcl-3 deficiency did not significantly affect anti-islet Th1 or Th2 autoimmune responses, but markedly increased inflammatory chemokine and T helper 17 (Th17)-type cytokine expression. Upon transfection, Bcl-3 significantly inhibited the promoter activities of inflammatory chemokine and cytokine genes.</jats:p></jats:sec><jats:sec><jats:title>CONCLUSIONS</jats:title><jats:p>These results indicate that in addition to mediating lymphoid organogenesis, Bcl-3 prevents autoimmune diabetes by inhibiting inflammatory chemokine and cytokine gene transcription. Thus, a single Bcl3 gene mutation leads to both autoimmunity and immunodeficiency.</jats:p></jats:sec> |
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| Umfang: | 2549-2557 |
| ISSN: |
0012-1797
1939-327X |
| DOI: | 10.2337/db10-0480 |