Rosiglitazone, a PPARγ ligand, modulates signal transduction pathways during the development of acute TNBS-induced colitis in rats
Introduction
The peroxisome proliferator-activated receptors (PPAR) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are related to retinoid, steroid and thyroid hormone receptors. PPARs regulate gene expression by binding to retinoid X receptors (RXR) as heterodimers. To date, three isoforms, encoded by separated genes, have been identified: PPARα, PPARβ or PPARδ and PPARγ. PPARγ has classically been characterized for its implications in adipocyte differentiation and fat metabolism. Recent studies have shown that thiazolidindiones (TZD) may participate in inflammation control, especially in regulating the production of immunomodulatory and inflammatory mediators (Cabrero et al., 2002, Na and Surh, 2003, Pershadsingh, 2004, Alarcón de la Lastra et al., 2004). Moreover, PPARγ induces a decrease in pro-inflammatory cytokines expression by antagonizing the activities of c-jun-NH2-terminal kinase (JNK) and p38 MAPK in vivo (Desreumaux et al., 2001) and interfering with the transcription factor activation such as nuclear factor NF-κB, signal transducers and transcription activators (STAT), activating protein 1 (AP-1), and the nuclear factor of activated T-cells (NFAT), all of which regulate cytokine gene expression (Dubuquoy et al., 2002).
PPARγ is highly expressed in the colon, mainly in the crypts and surface of epithelial cells (Lytle et al., 2005), as well as in macrophages and T and B lymphocytes (Desreumaux et al., 2001, Lytle et al., 2005); however, its levels are decreased during chronic inflammation in humans and animals (Lefebvre et al., 1999, Katayama et al., 2003).
Ulcerative colitis is a non-specific inflammatory disorder involving primarily the mucosa and submucosa of the colon. Activated immune cells, mainly represented by neutrophils, macrophages, and cytotoxic T cells, play the role of aggressors that attack and destroy the intestinal barrier directly through physical contact or indirectly through the release of reactive oxygen and nitrogen metabolites. Reactive oxygen species are now increasingly recognized to be involved in cell growth, signalling and gene expression (Szanto et al., 2005). Furthermore, reactive oxygen species can activate diverse downstream signalling pathways, such as mitogen-activated protein kinases (MAPKs) or the transcription factor nuclear factor kappa B (NF-κB), thus modulating a number of different steps in the inflammatory cascade. These include production of pro-inflammatory cytokines (tumour necrosis factor alpha (TNF-α), interleukin (IL)-1β, interferon (INF)-γ IL-12, and IL-6) in different cell-types, degranulation of neutrophils, as well as the expression of important determining parameters of colonic damage i.e. cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) (Dubuquoy et al., 2002, Collino et al., 2006).
There are recent reports which document that PPARγ ligands decrease the degree of inflammation associated with experimental colitis. For example, we have previously reported that the PPARγ ligand, rosiglitazone, was able to suppress the degree of inflammation associated with chronic experimental colitis (Sanchez-Hidalgo et al., 2005). Cuzzocrea et al. (2003) demonstrated the protective effects of the endogenous PPARγ agonist, 15d-PGJ2, on colon damage caused by dinitrobenzene sulfonic acid in the rat. Interestingly, Desreumaux et al. described the effectiveness of PPARγ ligands for the amelioration of 2,4,6,-trinitrobenzene sulfonic acid (TNBS)-induced acute colitis in PPARγ+/− mice. Similarly, Su et al. (1999) and Takagi et al. (2002) reported the attenuation of colonic inflammation by troglitazone in mice. Basing ourselves upon these data there is no doubt that PPARγ may play a central role in anti-inflammatory responses in the colon. Nevertheless, there are many interesting questions regarding the molecular mechanisms for action and signalling pathways in ulcerative colitis. On the other hand, the novelty of this study is that the effects of the TZD, rosiglitazone, in colonic mucosa under acute TNBS-induced colitis in rats were tested for the first time as well as the involvement of the signalling pathways implicated in experimental acute inflammatory disease development. The inflammatory response was assessed by histology and myeloperoxidase (MPO) activity, as an index of quantitative inflammation and neutrophil infiltration in the mucosa. TNF-α production and histological and histochemical analysis lesions were also carried out. Prostaglandin (PG)E2 generation and COX-1, COX-2, nuclear transcription factor NF-κB p65 and MAPK p38 expression were analyzed in order to gain a better insight into the action mechanism(s) of the observed protective effects of rosiglitazone. Finally, since PPARγ agonists have been found to modulate apoptosis in colitis-related colon carcinogenesis (Sanchez-Hidalgo et al., 2005, Kohno et al., 2001) our aim was to study their effects on acute TNBS-induced colitis in rats.
Section snippets
Experimental animals
Male Wistar rats supplied by Animal Services, Faculty of Medicine, University of Seville, Spain, and weighing 180–220 g, were placed in a controlled room (temperature 24–25 °C, humidity 70–75%, lighting regimen of 12L/12D) and were fed a normal laboratory diet (Panlab, Barcelona, Spain). Rats were deprived of food for 24 h prior to the induction of colitis, but were allowed free access to tap water throughout. 14 animals were randomly assigned to each group. Experiments followed a protocol
Protective effects of rosiglitazone in acute TNBS-induced colitis in rats
48 h after intracolonic administration of TNBS, rats showed postration, piloerection and hypomotility. Macroscopic inspection of the cecum, colon and rectum showed evidence of severe colonic mucosal damage, with edema, deep ulcerations and haemorrhage (Fig. 1A). Lesions in the distal colon were quantified using a macroscopic damage score (mean: 9.66 ± 0.66) (Fig. 1B). Control animals underwent severe anorexia with a marked body weight loss compared with the sham animals. A significant increase of
Discussion
In the present study we have demonstrated for first time that the PPARγ ligand, rosiglitazone, attenuated TNBS-induced acute colonic injury in rats. There was an attenuation of morphological signs of cell damage, the colonic mucosa showed ulcers at the beginning of reepithelization and healing process. The decrease in the extent of colitis was accompanied by a lower body weight loss in the animals and a decrease of adhesions between the colon and adjacent organs. The presence of adhesions,
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