Effects of AP-1 and NF-κB inhibitors on colonic endocrine cells in rats with TNBS-induced colitis

Abstract

Interactions between intestinal neuroendocrine peptides/amines and the immune system appear to have an important role in the pathophysiology of inflammatory bowel disease (IBD). The present study investigated the effects of activator protein (AP)-1 and nuclear factor (NF)-κB inhibitors on inflammation-induced alterations in enteroendocrine cells. A total of 48 male Wistar rats were divided into the following four groups (n=12 rats/group): Control, trinitrobenzene sulfonic acid (TNBS)-induced colitis only (TNBS group), TNBS-induced colitis with 3-[(dodecylthiocarbonyl)-methyl]-glutarimide (DTCM-G) treatment (DTCM-G group), and TNBS-induced colitis with dehydroxymethylepoxyquinomicin (DHMEQ) treatment (DHMEQ group). A total of 3 days following administration of TNBS, the rats were treated as follows: The control and TNBS groups received 0.5 ml vehicle (0.5% carboxymethyl cellulose; CMC), respectively; the DTCM-G group received DTCM-G (20 mg/kg body weight) in 0.5% CMC; and the DHMEQ group received DHMEQ (15 mg/kg body weight) in 0.5% CMC. All injections were performed intraperitoneally twice daily for 5 days. The rats were sacrificed, and tissue samples obtained from the colon were examined histopathologically and immunohistochemically. Inflammation was evaluated using a scoring system. In addition, the sections were immunostained for chromogranin A (CgA), serotonin, peptide YY (PYY), oxyntomodulin, pancreatic polypeptide (PP) and somatostatin, and immunostaining was quantified using image-analysis software. The density of cells expressing CgA, PYY and PP was significantly lower in the TNBS group compared with in the control group, whereas the density of cells expressing serotonin, oxyntomodulin and somatostatin was significantly higher in the TNBS group compared with in the control group. None of the endocrine cell types differed significantly between the control group and either the DTCM-G or DHMEQ groups. All of the colonic endocrine cell types were affected in rats with TNBS-induced colitis. The expression density of these endocrine cell types was restored to control levels following treatment with AP-1 or NF-κB inhibitors. These results indicated that the immune system and enteroendocrine cells interact in IBD.

Enteroendocrine cells-sensory sentinels of the intestinal environment and orchestrators of mucosal immunity

“…Numerous of the above studies correlate inflammation to alterations in eecs, and changes in IBD-mouse models are prevented with prior treatment of NFkb or AP-1 inhibitors, which although not exclusively activated by immune cells, suggests the changes as immune driven. 148,223 There is a close physical association of immune cells with eecs 224 and infection driven 5-HT þ cell hyperplasia observed during Citrobacter rodentium infection is absent in severe combined immunodeficiency (SCID) mice, 225 as is the CCK and 5-HT þ cell hyperplasia seen in helminth infection. 195,226 5-HT þ cell increases seen during T. muris infection are also driven by specific T-helper (Th)2 CD4 þ T-cell responses.…”

Gastrointestinal neuroendocrine peptides/amines in inflammatory bowel disease

“…Patients with IBD exhibit elevated concentrations of fecal CgA and secretogranins[ 242 , 243 ]. The CgA cell density is increased in patients with IBD, and in animal models of human UC and CD, with the exception of trinitrobenzene sulfonic acid (TNBS)-induced colitis[ 9 , 117 , 244 - 248 ] (Figure 3 ). The administration of the proinflammatory cytokines INFγ and TNFα and the induction of colitis by dextran sodium sulfate (DSS) in mice were found to increase the number of CgA cells[ 249 ].…”

“…Whereas the density of oxyntomodulin-containing cells is increased in patients with CD and in both DSS- and TNBS-induced colitis, and in IL-2 gene-knockout mice, it is unchanged in patients with UC[ 118 , 244 , 251 , 258 ]. The PP cell density is decreased in patients with CD and in colitis induced by either DSS, or TNBS in rats[ 117 , 245 , 248 ].…”

“…Whereas changes in GI endocrine cells do occur in UC, CD, lymphocytic colitis, and animal models of human IBD, the nature of these changes differ between the different IBDs and animal models of human IBD[ 9 , 117 , 244 - 248 , 250 , 259 ]. The changes in GI endocrine cells can be explained by two different mechanisms: abnormal stem cell clonogenic and differentiation progeny toward endocrine cells activities (Figure 6 ), and switching on and off of the expression of certain GI NEPA (Figure 7 ).…”

Alliin, a garlic organosulfur compound, ameliorates gut inflammation through MAPK-NF-κB/AP-1/STAT-1 inactivation and PPAR-γ activation

“…Several studies have been shown that AP-1 activation be regulated by modulating the transcription of genes encoding the AP-1 subunits or by post-translational changes of AP-1 (including the phosphorylation of AP-1) or by changes in specific interactions between AP-1 and other transcription factors and cofactors and is associated with inflammation [77][78][79]. A study performed in rats with TNBS induced colitis indicated that treatment with AP-1 inhibitor DTCM-G and NF-B inhibitor DHMEQ restored the density of colonic endocrine cells to normal on colonic endocrine cells in rats with TNBS-induced colitis [77]. Moriyama et al demonstrated that double-strand decoy oligodeoxynucleotide targeting AP-1 and effectively inhibit AP-1 transcriptional activity to attenuated intestinal inflammation associated with DSS-induced colitis in mice [78].…”