ABSTRACT
Title
Differential roles of microsomal Prostaglandin E Synthase-1 inmurine colitis
Authors
A. Bruno
Doctorate School in Clinical and Experimental Medical Science
Dept. of Medicine and Aging, “G.d’Annunzio” University and CeSI, Chieti (Italy)
Doctorate School in Clinical and Experimental Medical Science
Dept. of Medicine and Aging, “G.d’Annunzio” University and CeSI, Chieti (Italy)
Abstract
The roles of prostanoids in inflammatory bowel diseases(IBD) are not completely clarified. Prostaglandin(PG)E2 is generated at sites of inflammation in substantial amounts, by conversion of arachidonic acid(AA) via cyclooxygenase(COX)-2/microsomal PGE2 synthase(mPGES-1) pathway, and can mediate many of the pathologic features of inflammation(1). However, PGE2 may also promote resolution of inflammation(2). Recently, it has been shown that PGD2 derived from lipocalin-type PGD synthase(L-PGDS)-expressing cells plays proinflammatory roles in murine colitis(3). The aims of this study were: i) to characterize prostanoid[PGE2, PGD2, TXA2 and prostacyclin(PGI2)] biosynthesis in vivo in a murine model of dextran sulfate sodium(DSS)-induced colitis both in the acute phase(after 3 days) and in the resolution phase(24h after DSS discontinuation) of the disease, by correlating prostanoid generation to clinical and histological parameters; ii)to evaluate the impact ofmPGES-1 deletion on prostanoid generation and clinical and histological parameters of the disease. mPGES-1-/- and wild type(WT) mice received DSS 2% in drinking water from day(d)0 to d5. Colitis was evaluated by assessment of blood in stool and stool consistency and histological analysis of colon samples. In 24h urine collected at baseline, in acute phase(d3-4) and in resolution phase(d5-6), systemic biosynthesis of 11alpha-hydroxy-9, 15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid(PGE-M), 2,3-dinor-6-keto PGF1alpha(PGI-M), 2,3-dinor- thromboxane B2(TX-M) and 11,15-Dioxo-9alpha -hydroxy-2,3,4,5-tetranorprostan-1,20-dioic acid(PGD-M), as indices of PGE2, PGI2, TXB2 and PGD2 biosynthesis in vivo, respectively, were assessed by liquid-chromatography-mass spectrometry(4). mPGES-1 deletion was associated with worsening of DSS-induced acute colitis versus WT mice. At 24h after DSS discontinuation, in mPGES-1-/-mice,improvement of clinical symptoms and histologic changes(such as ulcerative lesions and crypt loss) were detected.
As shown in the table, in WT mice with DSS-induced colitis, PGE2 generation was significantly increased versus untreated mice both at 4d of DSS treatment and at 24h after DSS discontinuation. mPGES-1 deletion caused a significant reduction of PGE-M urinary levels at each time-point versus WT mice. PGD-M was significant increased versus control mice at 4d of DSS treatment both in WT and in mPGES-1-/-mice but not in the resolution phase of intestinal inflammation. In mPGES-1-/-mice, PGD-M tended to be higher than in WT mice. PGI-M was significantly higher than in untreated WT mice only at 24h after DSS discontinuation. TX-M was increased only in mPGES-1-/-mice at 24h after DSS discontinuation. This study showed that in the acute phase of DSS-induced colitis, both PGE2 and PGD2 were increased and deletion of mPGES-1 augmented PGD2 and accelerated the development of the disease. This finding is consistent with a role of mPGES-1-derived PGE2 to maintain intestinal homeostasis by keeping mucosal integrity and down-regulating immune response(5) and with a pro-inflammatory action of PGD2(3). During the resolution phase of the disease enhanced biosynthesis of PGI2 was detected and mPGES-1 deletion was associated with reduced ulcerative lesions and reduced crypt loss. This finding may suggest that in this setting PGE2 altered the homeostatic balance between proliferation and apoptosis essential to normal gut morphology and function.
1) Murakami et al. 2000 JBC 275:32783-92
2) Bandeira-Mela et al. 2000 J Immunol164:1029-36
3) Hokari et al. 2011 AJP-GILiver Physiol300:G401-8
4) Wang et al. 2008 Circulation 117:1302-9
5) Kabashima et al. 2002 JCI 109:883–893
| wT mice |
mPGES-1-/- mice |
|||||
|
DSS(0-5d) |
DSS(0-5d) | |||||
|
values % of control (mean±SD) |
Control | Day 4 | Day 6 | |||
| Control | Day 4 | Day 6 | ||||
| PGE-M | 100±37 | 287±68** | 204±100** | 58±21 | 100±50 | 70±30 |
| PGD-M | 100±40 | 170±30* | 129±51 | 145±70* | 208±110* | 146±115 |
| TX-M | 100±26 | 84±16 | 107±40 | 119±26 | 114±20 | 180±53* |
| PGI-M | 100±59 | 113±59 | 237±221* | 140±70 | 141±56 | 206±77* |
| P values vs control WT: **P<0.01;*P<0.05 | ||||||
As shown in the table, in WT mice with DSS-induced colitis, PGE2 generation was significantly increased versus untreated mice both at 4d of DSS treatment and at 24h after DSS discontinuation. mPGES-1 deletion caused a significant reduction of PGE-M urinary levels at each time-point versus WT mice. PGD-M was significant increased versus control mice at 4d of DSS treatment both in WT and in mPGES-1-/-mice but not in the resolution phase of intestinal inflammation. In mPGES-1-/-mice, PGD-M tended to be higher than in WT mice. PGI-M was significantly higher than in untreated WT mice only at 24h after DSS discontinuation. TX-M was increased only in mPGES-1-/-mice at 24h after DSS discontinuation. This study showed that in the acute phase of DSS-induced colitis, both PGE2 and PGD2 were increased and deletion of mPGES-1 augmented PGD2 and accelerated the development of the disease. This finding is consistent with a role of mPGES-1-derived PGE2 to maintain intestinal homeostasis by keeping mucosal integrity and down-regulating immune response(5) and with a pro-inflammatory action of PGD2(3). During the resolution phase of the disease enhanced biosynthesis of PGI2 was detected and mPGES-1 deletion was associated with reduced ulcerative lesions and reduced crypt loss. This finding may suggest that in this setting PGE2 altered the homeostatic balance between proliferation and apoptosis essential to normal gut morphology and function.
1) Murakami et al. 2000 JBC 275:32783-92
2) Bandeira-Mela et al. 2000 J Immunol164:1029-36
3) Hokari et al. 2011 AJP-GILiver Physiol300:G401-8
4) Wang et al. 2008 Circulation 117:1302-9
5) Kabashima et al. 2002 JCI 109:883–893