Abstract
The objectives of this study were to (1) assess the role of the 26S proteasome complex in regulating the expression of the inducible isoform of nitric oxide synthase (iNOS) and vascular cell adhesion molecule-1 (VCAM-1) in a model of chronic granulomatous colitisin vivo and (2) determine the role of the proteasome in regulating the inflammatory response observed in this model of chronic gut inflammation. The selective proteasome inhibitor MG-341 (0.3 mg/kg) was administered by gavage beginning immediately before the induction of colitis and continuing daily thereafter for the entire 14-day experimental period. We found that chronic proteasome inhibition using MG-341 significantly attenuated the peptidoglycan/polysaccharide (PG/PS)-induced up-regulation of iNOS in the colon and spleen and the consequent increase in plasma levels of nitrate and nitrite. Furthermore, we found that the proteasome inhibitor suppressed the up-regulation of the adhesion molecule VCAM-1 in the colon. We also found that MG-341 attenuated PG/PS-induced increases in macroscopic colonic inflammation, bowel wall thickness, colonic dry weight and colonic MPO activity. Treatment with MG-341 also significantly reduced PG/PS-induced increases in macroscopic spleen inflammation, spleen weight and spleen MPO activity. We conclude that the 26S proteasome complex plays an important role in regulating the PG/PS-induced up-regulation of iNOS and VCAM-1 in vivo and appears to be important in regulating colonic and splenic inflammation.
Footnotes
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Send reprint requests to: Elaine M. Conner, Ph.D., Department of Molecular and Cellular Physiology, Louisiana State University Medical Center, P.O. Box 33932, 1501 Kings Highway, Shreveport, LA 71130.
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↵1 This work was supported by National Institutes of Health Grants DK47663 and PO1-DK43785 (Project 6 and the Morphology Core).
- Abbreviations:
- PG/PS
- peptidoglycan/polysaccharide
- MPO
- myeloperoxidase
- iNOS
- inducible nitric oxide synthase
- NO
- nitric oxide
- IBD
- inflammatory bowel disease
- VCAM
- vascular cell adhesion molecule
- IκB
- inhibitor-κB
- ICAM
- intercellular adhesion molecule
- HEPES
- 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
- SDS
- sodium dodecyl sulfate
- NF-κB
- nuclear factor-κB
- Received January 6, 1997.
- Accepted May 29, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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