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Osteopontin mediates Stat1 degradation to inhibit iNOS transcription in a cecal ligation and puncture model of sepsis.

Publication ,  Journal Article
Guo, H; Wai, PY; Mi, Z; Gao, C; Zhang, J; Kuo, PC
Published in: Surgery
August 2008

BACKGROUND: Osteopontin (OPN) represses inducible nitric oxide synthase (iNOS) expression by increasing ubiquitin (Ub)-proteasome degradation of Stat1, a critical transcription factor for iNOS expression. We investigated the in vivo relevance of our findings in a cecal ligation and puncture model. METHODS AND RESULTS: A total of 129 wild-type (WT; n = 24) and OPN null (n = 24) mice were used. Bone marrow macrophages and whole liver tissue were isolated. iNOS and phosphorylated Stat-1 (P-Stat1) protein were significantly greater in OPN null than WT. Cecal ligation and puncture increased Ub-P-Stat1; Ub-P-Stat1 was significantly less in OPN null than WT. In chromatin immunoprecipitation assays, P-Stat1 binding to the iNOS promoter was increased in OPN null. Ex vivo studies with bone marrow macrophages were performed with MG132 (10 microM), an inhibitor of 26S proteasome function, and/or exogenous OPN (50 microM). Ub-P-Stat1 was decreased in OPN null bone marrow macrophages treated with LPS; iNOS was increased. Exogenous OPN or MG132 restored Ub-P-Stat1 and iNOS to levels seen in WT. Our results indicate that absence of OPN does the following: (1) increases iNOS and P-Stat1 protein, (2) decreases ubiquitination and degradation of P-Stat1, and (3) increases iNOS transcription. CONCLUSIONS: We conclude that OPN downregulates iNOS expression by accelerating ubiquitination and degradation of Stat1.

Duke Scholars

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Published In

Surgery

DOI

EISSN

1532-7361

Publication Date

August 2008

Volume

144

Issue

2

Start / End Page

182 / 188

Location

United States

Related Subject Headings

  • Ubiquitin
  • Surgery
  • Sepsis
  • STAT1 Transcription Factor
  • Promoter Regions, Genetic
  • Osteopontin
  • Nitric Oxide Synthase Type II
  • Mice, Knockout
  • Mice
  • Male
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Guo, H., Wai, P. Y., Mi, Z., Gao, C., Zhang, J., & Kuo, P. C. (2008). Osteopontin mediates Stat1 degradation to inhibit iNOS transcription in a cecal ligation and puncture model of sepsis. Surgery, 144(2), 182–188. https://doi.org/10.1016/j.surg.2008.03.007
Guo, Hongtao, Philip Y. Wai, Zhiyong Mi, Chengjiang Gao, Jinping Zhang, and Paul C. Kuo. “Osteopontin mediates Stat1 degradation to inhibit iNOS transcription in a cecal ligation and puncture model of sepsis.Surgery 144, no. 2 (August 2008): 182–88. https://doi.org/10.1016/j.surg.2008.03.007.
Guo H, Wai PY, Mi Z, Gao C, Zhang J, Kuo PC. Osteopontin mediates Stat1 degradation to inhibit iNOS transcription in a cecal ligation and puncture model of sepsis. Surgery. 2008 Aug;144(2):182–8.
Guo, Hongtao, et al. “Osteopontin mediates Stat1 degradation to inhibit iNOS transcription in a cecal ligation and puncture model of sepsis.Surgery, vol. 144, no. 2, Aug. 2008, pp. 182–88. Pubmed, doi:10.1016/j.surg.2008.03.007.
Guo H, Wai PY, Mi Z, Gao C, Zhang J, Kuo PC. Osteopontin mediates Stat1 degradation to inhibit iNOS transcription in a cecal ligation and puncture model of sepsis. Surgery. 2008 Aug;144(2):182–188.
Journal cover image

Published In

Surgery

DOI

EISSN

1532-7361

Publication Date

August 2008

Volume

144

Issue

2

Start / End Page

182 / 188

Location

United States

Related Subject Headings

  • Ubiquitin
  • Surgery
  • Sepsis
  • STAT1 Transcription Factor
  • Promoter Regions, Genetic
  • Osteopontin
  • Nitric Oxide Synthase Type II
  • Mice, Knockout
  • Mice
  • Male