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Vol. 282, Issue 3, 1615-1622, 1997
Departments of
Molecular and Cellular Physiology (E.M.C., J.M.D.,
F.S.L., D.Y.K., M.B.G.) and
Medicine (J.W.F., R.E.W.), Louisiana State
University Medical Center, Shreveport, Louisiana, and
ProScript, Inc.,
Cambridge, Massachusetts (S.B., V.J.P).
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 colitis
in 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.
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