NFκB1 (p50)-deficient mice are not susceptible to multiple low-dose streptozotocin-induced diabetes

J. G. Mabley, G. Haskó, L. Liaudet, F. Soriano, G. J. Southan, A. L. Salzman, Csaba Szabo

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Insulin-dependent diabetes mellitus (IDDM) is a disease characterized by the autoimmune destruction of the pancreatic β-cells, which requires the expression of a number of immune-related genes including major histocompatibility complex proteins, cytokines, chemokines, and cytotoxic enzymes, many of which are regulated by the transcription factor, NFκB. Inhibition of the entire NFκB family of transcription factors may be harmful, as these factors are involved in many normal physiological processes. However, identifying and targeting specific NFκB subunits critical for the pathogenesis of disease may prove to be valuable in designing new therapeutic strategies. To assess the potential role of the NFκB subunit, p50, in the development of IDDM, mice with gene disruption for NFκB (p50) were investigated for susceptibility to IDDM. We found that p50-deficient mice were fully resistant against multiple low-dose streptozotocin-induced diabetes, a model of diabetes with a strong autoimmune component. The site of involvement of NFκB (p50) lies at an early, critical juncture of immune activation and proinflammatory mediator production, because: (1) isolated islets of Langerhans from NFκB (p50)-deficient mice were not protected from the islet dysfunction induced by in vitro application of proinflammatory cytokines; (2) p50-deficient mice were not resistant to diabetes induced by a single high dose of streptozotocin, a model with a large oxidant component and no autoimmune involvement: and (3) diabetes induced up-regulation of nitric oxide and interleukin-12 was blocked in the p50-deficient mice. Our data suggest that NFκB (p50) has an essential role in the development of autoimmune diabetes. Selective therapeutic blockade of this subunit may be beneficial in preventing IDDM.

Original languageEnglish (US)
Pages (from-to)457-464
Number of pages8
JournalJournal of Endocrinology
Volume173
Issue number3
DOIs
StatePublished - 2002
Externally publishedYes

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Experimental Diabetes Mellitus
Type 1 Diabetes Mellitus
Transcription Factors
Physiological Phenomena
Cytokines
Interleukin-12
Streptozocin
Major Histocompatibility Complex
Islets of Langerhans
Chemokines
Oxidants
Genes
Autoimmune Diseases
Nitric Oxide
Up-Regulation
Enzymes
Therapeutics
Proteins

ASJC Scopus subject areas

  • Endocrinology

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NFκB1 (p50)-deficient mice are not susceptible to multiple low-dose streptozotocin-induced diabetes. / Mabley, J. G.; Haskó, G.; Liaudet, L.; Soriano, F.; Southan, G. J.; Salzman, A. L.; Szabo, Csaba.

In: Journal of Endocrinology, Vol. 173, No. 3, 2002, p. 457-464.

Research output: Contribution to journalArticle

Mabley, J. G. ; Haskó, G. ; Liaudet, L. ; Soriano, F. ; Southan, G. J. ; Salzman, A. L. ; Szabo, Csaba. / NFκB1 (p50)-deficient mice are not susceptible to multiple low-dose streptozotocin-induced diabetes. In: Journal of Endocrinology. 2002 ; Vol. 173, No. 3. pp. 457-464.
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