Rosiglitazone, a PPARgamma ligand, modulates signal transduction pathways during the development of acute TNBS-induced colitis in rats.
Recent studies have shown that peroxisome proliferator-activated receptor gamma (PPARgamma), a highly nuclear receptor expressed in the colon, may participate in the control of inflammation, especially in regulating the production of immunomodulatory and inflammatory mediators, cellular proliferation and apoptosis. In order to delve into the anti-inflammatory mechanisms and signalling pathways of PPARgamma agonists, we have studied the effects of rosiglitazone, a PPARgamma agonist on the extent and severity of acute ulcerative colitis caused by intracolonic administration of 2,4,6-trinitribenzene sulfonic acid (TNBS) in rats. The inflammatory response was assessed by gross appearance, myeloperoxidase (MPO) activity, tumour necrosis factor alpha (TNF-alpha) levels and a histological study of the lesions. We determined prostaglandin E2 production as well as the cyclooxygenases (COX)-1 and -2 expressions by immunohistochemistry and Western blotting. The nuclear factor kappa (NF-kappaB) p65 and p38 mitogen-activated protein kinase (MAPK) expression levels were also measured by Western blotting. Finally, since PPARgamma agonists modulate apoptosis, we tried to clarify its effects under early acute inflammatory conditions. Inflammation following TNBS induction was characterized by increased colonic wall thickness, edema, diffuse inflammatory cells infiltration, necrosis reaching an ulcer index (UI) of 9.66+/-0.66 cm(2) and increased MPO activity and TNF-alpha colonic levels. Rosiglitazone treatment significantly reduced the morphological alteration associated with TNBS administration and the UI with the highest dose. In addition, the degree of neutrophil infiltration and the cytokine levels were significantly ameliorated. Rosiglitazone significantly reduced the rise in the prostaglandin (PG) E(2) generation compared with TNBS group. The COX-1 levels remained stable throughout the treatment in all groups. The COX-2 expression was elevated in TNBS group; however rosiglitazone administration reduced the COX-2 overexpression. A high expression of NF-kappaB p65 and p38 MAPK proteins appeared in colon mucosa from control TNBS-treated rats; nevertheless, PPARgamma agonist treatment drastically decreased them. There were no significant changes in apoptosis after rosiglitazone treatment when compared to TNBS group. In conclusion, rosiglitazone seems to modulate the acute colitis through NF-kappaB p65 and p38 MAPK signalling pathways.
Sánchez-Hidalgo
Marina
M
Department of Pharmacology, University of Sevilla, Profesor García González Street 2, 41012 Seville, Spain.
Martín
Antonio Ramon
AR
Villegas
Isabel
I
de la Lastra
Catalina Alarcón
CA
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000188:drug therapy*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D015151:Immunoblotting; D007249:Inflammation / Q000188:drug therapy*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009504:Neutrophils; D047495:PPAR gamma / Q000819:agonists; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects*; D045162:Thiazolidinediones / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000187:drug effects / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism
D016207:Cytokines; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; D014302:Trinitrobenzenesulfonic Acid; D009195:Peroxidase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone