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Stable expression of manganese superoxide dismutase (MnSOD) in insulinoma cells prevents IL-1beta- induced cytotoxicity and reduces nitric oxide production.

Publication ,  Journal Article
Hohmeier, HE; Thigpen, A; Tran, VV; Davis, R; Newgard, CB
Published in: J Clin Invest
May 1, 1998

The fact that insulin-producing islet beta-cells are susceptible to the cytotoxic effects of inflammatory cytokines represents a potential hinderance to the use of such cells for transplantation therapy of insulin-dependent diabetes mellitus (IDDM). In the current study, we show that IL-1beta induces destruction of INS-1 insulinoma cells, while having no effect on a second insulinoma cell line RIN1046-38 and its engineered derivatives, and that this difference is correlated with a higher level of expression of manganese superoxide dismutase (MnSOD) in the latter cells. Stable overexpression of MnSOD in INS-1 cells provides complete protection against IL-1beta-mediated cytotoxicity, and also results in markedly reduced killing when such cells are exposed to conditioned media from activated human or rat PBMC. Further, overexpression of MnSOD in either RIN- or INS-1-derived lines results in a sharp reduction in IL-1beta-induced nitric oxide (NO) production, a finding that correlates with reduced levels of the inducible form of nitric oxide synthase (iNOS). Treatment of INS-1 cells with L-NMMA, an inhibitor of iNOS, provides the same degree of protection against IL-1beta or supernatants from LPS-activated rat PBMC as MnSOD overexpression, supporting the idea that MnSOD protects INS-1 cells by interfering with the normal IL-1beta-mediated increase in iNOS. Because NO and its derivatives have been implicated as critical mediators of beta-cell destruction in IDDM, we conclude that well regulated insulinoma cell lines engineered for MnSOD overexpression may be an attractive alternative to isolated islets as vehicles for insulin replacement in autoimmune diabetes.

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Published In

J Clin Invest

DOI

ISSN

0021-9738

Publication Date

May 1, 1998

Volume

101

Issue

9

Start / End Page

1811 / 1820

Location

United States

Related Subject Headings

  • omega-N-Methylarginine
  • Tumor Cells, Cultured
  • Superoxide Dismutase
  • Recombinant Proteins
  • Rats
  • RNA, Messenger
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase
  • Nitric Oxide
  • Islets of Langerhans
 

Citation

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Hohmeier, H. E., Thigpen, A., Tran, V. V., Davis, R., & Newgard, C. B. (1998). Stable expression of manganese superoxide dismutase (MnSOD) in insulinoma cells prevents IL-1beta- induced cytotoxicity and reduces nitric oxide production. J Clin Invest, 101(9), 1811–1820. https://doi.org/10.1172/JCI1489
Hohmeier, H. E., A. Thigpen, V. V. Tran, R. Davis, and C. B. Newgard. “Stable expression of manganese superoxide dismutase (MnSOD) in insulinoma cells prevents IL-1beta- induced cytotoxicity and reduces nitric oxide production.J Clin Invest 101, no. 9 (May 1, 1998): 1811–20. https://doi.org/10.1172/JCI1489.
Hohmeier, H. E., et al. “Stable expression of manganese superoxide dismutase (MnSOD) in insulinoma cells prevents IL-1beta- induced cytotoxicity and reduces nitric oxide production.J Clin Invest, vol. 101, no. 9, May 1998, pp. 1811–20. Pubmed, doi:10.1172/JCI1489.

Published In

J Clin Invest

DOI

ISSN

0021-9738

Publication Date

May 1, 1998

Volume

101

Issue

9

Start / End Page

1811 / 1820

Location

United States

Related Subject Headings

  • omega-N-Methylarginine
  • Tumor Cells, Cultured
  • Superoxide Dismutase
  • Recombinant Proteins
  • Rats
  • RNA, Messenger
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase
  • Nitric Oxide
  • Islets of Langerhans