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Infliximab and etanercept are equally effective in reducing enterocyte APOPTOSIS in experimental colitis.

Fries W, Muja C, Crisafulli C, Costantino G, Longo G, Cuzzocrea S, Mazzon E - Int J Med Sci (2008)

Bottom Line: Circulating TNF-alpha levels were effectively reduced by IFX and ETC (p<0.01, both) at 3 and 6 h.These alterations were prevented by both anti-TNF strategies, and in TNFR-1(-/-) animals.Both anti-TNF strategies, IFX and ETC, were equally effective in suppressing enterocyte apoptosis, most likely by inactivation of circulating TNF-alpha.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Medicina Interna e Terapia Medica, Sezione di Farmacologia, Università di Messina, Messina, Italy. fwalter@unime.it

ABSTRACT
Loss of epithelial barrier integrity is considered an early step in the pathogenesis of Crohn's disease (CD), and the rate of enterocyte apoptosis is one of the determinants of the intestinal barrier function. Tumor necrosis factor-alpha (TNF-alpha), one of the major proinflammatory mediators in CD, is one of the extrinsic signals which initiate apoptosis of enterocytes. The aim of this study was to investigate the early effects of experimental colitis on enterocyte apoptosis, and the effects of two anti-TNF treatments, infliximab (IFX) and etanercept (ETC). In addition, the importance of receptor I for TNF was tested in TNFR-1(-/- )mice. Circulating TNF-alpha levels were effectively reduced by IFX and ETC (p<0.01, both) at 3 and 6 h. Apoptosis of the ileal enterocytes, assessed by TUNEL staining, staining for Fas-ligand, and bax, increased at 3 and 6h. These alterations were prevented by both anti-TNF strategies, and in TNFR-1(-/-) animals. The anti-apoptotic protein Bcl-2 was expressed in the ileal epithelium under control conditions, but was suppressed in DNB-colitis. Expression of Bcl-2 was maintained in both anti-TNF treatments and TNFR-1(-/-) mice.DNB colitis induced a very early, rapid increase of enterocyte apoptosis. Both anti-TNF strategies, IFX and ETC, were equally effective in suppressing enterocyte apoptosis, most likely by inactivation of circulating TNF-alpha.

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Western-blot analysis of ileal concentrations of bax three hours (a; upper panel) and 6 hours (b; lower panel) in control animals with sham colitis (sham WT), in control TNFR-1-/- animals and sham colitis (sham TNF-α KO), in animals treated with ETC or IFX alone without colitis, in animals with DNBS/ethanol colitis and sham treatment (DNBS WT), in TNFR-1-/- animals with colitis (DNBS TNF-α KO), and in animals with colitis and ETC or IFX treatment; protein expression of bax was significantly increased in DNBS colitis compared with all other conditions. At 6 h in TNFR-1-/- animals with colitis traces of bax were detectable. These trace amounts were due to subepithelial bax expression.
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Figure 4: Western-blot analysis of ileal concentrations of bax three hours (a; upper panel) and 6 hours (b; lower panel) in control animals with sham colitis (sham WT), in control TNFR-1-/- animals and sham colitis (sham TNF-α KO), in animals treated with ETC or IFX alone without colitis, in animals with DNBS/ethanol colitis and sham treatment (DNBS WT), in TNFR-1-/- animals with colitis (DNBS TNF-α KO), and in animals with colitis and ETC or IFX treatment; protein expression of bax was significantly increased in DNBS colitis compared with all other conditions. At 6 h in TNFR-1-/- animals with colitis traces of bax were detectable. These trace amounts were due to subepithelial bax expression.

Mentions: Like Fas-L, bax was also not detectable in controls (fig 3 A,B), but was increased in animals with colitis (fig. 3 C,D), especially in the crypt compartment. Treatment with ETC (fig 3 E,F) and with IFX (fig. 3 G,H) and the absence of the receptor-1 for TNF-α (fig. 3 I,J) prevented the expression of bax in the ileal enterocytes. On Western-blot analysis (fig. 4) bax was expressed strongly in the ileal mucosa of animals with colitis at 3 and 6h. This increased expression was effectively prevented by both IFX and ETC. In TNFR-1-/- mice with colitis, some expression of bax in the subepithelial layer was present.


Infliximab and etanercept are equally effective in reducing enterocyte APOPTOSIS in experimental colitis.

Fries W, Muja C, Crisafulli C, Costantino G, Longo G, Cuzzocrea S, Mazzon E - Int J Med Sci (2008)

Western-blot analysis of ileal concentrations of bax three hours (a; upper panel) and 6 hours (b; lower panel) in control animals with sham colitis (sham WT), in control TNFR-1-/- animals and sham colitis (sham TNF-α KO), in animals treated with ETC or IFX alone without colitis, in animals with DNBS/ethanol colitis and sham treatment (DNBS WT), in TNFR-1-/- animals with colitis (DNBS TNF-α KO), and in animals with colitis and ETC or IFX treatment; protein expression of bax was significantly increased in DNBS colitis compared with all other conditions. At 6 h in TNFR-1-/- animals with colitis traces of bax were detectable. These trace amounts were due to subepithelial bax expression.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2452978&req=5

Figure 4: Western-blot analysis of ileal concentrations of bax three hours (a; upper panel) and 6 hours (b; lower panel) in control animals with sham colitis (sham WT), in control TNFR-1-/- animals and sham colitis (sham TNF-α KO), in animals treated with ETC or IFX alone without colitis, in animals with DNBS/ethanol colitis and sham treatment (DNBS WT), in TNFR-1-/- animals with colitis (DNBS TNF-α KO), and in animals with colitis and ETC or IFX treatment; protein expression of bax was significantly increased in DNBS colitis compared with all other conditions. At 6 h in TNFR-1-/- animals with colitis traces of bax were detectable. These trace amounts were due to subepithelial bax expression.
Mentions: Like Fas-L, bax was also not detectable in controls (fig 3 A,B), but was increased in animals with colitis (fig. 3 C,D), especially in the crypt compartment. Treatment with ETC (fig 3 E,F) and with IFX (fig. 3 G,H) and the absence of the receptor-1 for TNF-α (fig. 3 I,J) prevented the expression of bax in the ileal enterocytes. On Western-blot analysis (fig. 4) bax was expressed strongly in the ileal mucosa of animals with colitis at 3 and 6h. This increased expression was effectively prevented by both IFX and ETC. In TNFR-1-/- mice with colitis, some expression of bax in the subepithelial layer was present.

Bottom Line: Circulating TNF-alpha levels were effectively reduced by IFX and ETC (p<0.01, both) at 3 and 6 h.These alterations were prevented by both anti-TNF strategies, and in TNFR-1(-/-) animals.Both anti-TNF strategies, IFX and ETC, were equally effective in suppressing enterocyte apoptosis, most likely by inactivation of circulating TNF-alpha.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Medicina Interna e Terapia Medica, Sezione di Farmacologia, Università di Messina, Messina, Italy. fwalter@unime.it

ABSTRACT
Loss of epithelial barrier integrity is considered an early step in the pathogenesis of Crohn's disease (CD), and the rate of enterocyte apoptosis is one of the determinants of the intestinal barrier function. Tumor necrosis factor-alpha (TNF-alpha), one of the major proinflammatory mediators in CD, is one of the extrinsic signals which initiate apoptosis of enterocytes. The aim of this study was to investigate the early effects of experimental colitis on enterocyte apoptosis, and the effects of two anti-TNF treatments, infliximab (IFX) and etanercept (ETC). In addition, the importance of receptor I for TNF was tested in TNFR-1(-/- )mice. Circulating TNF-alpha levels were effectively reduced by IFX and ETC (p<0.01, both) at 3 and 6 h. Apoptosis of the ileal enterocytes, assessed by TUNEL staining, staining for Fas-ligand, and bax, increased at 3 and 6h. These alterations were prevented by both anti-TNF strategies, and in TNFR-1(-/-) animals. The anti-apoptotic protein Bcl-2 was expressed in the ileal epithelium under control conditions, but was suppressed in DNB-colitis. Expression of Bcl-2 was maintained in both anti-TNF treatments and TNFR-1(-/-) mice.DNB colitis induced a very early, rapid increase of enterocyte apoptosis. Both anti-TNF strategies, IFX and ETC, were equally effective in suppressing enterocyte apoptosis, most likely by inactivation of circulating TNF-alpha.

Show MeSH
Related in: MedlinePlus