All-Trans Retinoic Acid Modulates TLR4/NF-Κb

All-Trans Retinoic Acid Modulates TLR4/NF-κB Signaling Pathway Targeting TNF-αand Nitric Oxide Synthase 2 Expression in Colonic Mucosa during Ulcerative Colitis and Colitis Associated Cancer Hayet Rafa, Sarra Benkhelifa, Sonia Aityounes, Houria Saoula, Said Belhadef, Mourad Belkhelfa, Aziza Boukercha, Ryma Toumi, Imene Soufli, Olivier Moralès, et al. To cite this version: Hayet Rafa, Sarra Benkhelifa, Sonia Aityounes, Houria Saoula, Said Belhadef, et al.. All-Trans Retinoic Acid Modulates TLR4/NF-κB Signaling Pathway Targeting TNF-αand Nitric Oxide Syn- thase 2 Expression in Colonic Mucosa during Ulcerative Colitis and Colitis Associated Cancer. Media- tors of Inflammation, Hindawi Publishing Corporation, 2017, 2017, pp.1 - 16. 10.1155/2017/7353252. hal-03059784 HAL Id: hal-03059784 https://hal.archives-ouvertes.fr/hal-03059784 Submitted on 13 Dec 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Hindawi Mediators of Inﬂammation Volume 2017, Article ID 7353252, 16 pages http://dx.doi.org/10.1155/2017/7353252 Research Article All-Trans Retinoic Acid Modulates TLR4/NF-B Signaling Pathway Targeting TNF- and Nitric Oxide Synthase 2 Expression in Colonic Mucosa during Ulcerative Colitis and Colitis Associated Cancer Hayet Rafa,1,2 Sarra Benkhelifa,1,2 Sonia AitYounes,3 Houria Saoula,4 Said Belhadef,5 Mourad Belkhelfa,1 Aziza Boukercha,1 Ryma Toumi,1 Imene Soufli,1 Olivier Moralès,2 Yvan de Launoit,2 Hassen Mahfouf,5 M’hamed Nakmouche,4 Nadira Delhem,2 and Chafia Touil-Boukoffa1 1 Team: Cytokines and NO Synthases-Immunity and Pathogenesis, Laboratory of Cellular and Molecular Biology (LBCM), Faculty of Biological Science, University of Sciences and Technology (USTHB), Algiers, Algeria 2Institut de Biologie de Lille, UMR 8161, CNRS, Institut Pasteur de Lille, UniversiteLille-NorddeFrance,Lille,France´ 3Anatomic Pathology Service, Mustapha Pacha Hospital, Algiers, Algeria 4Department of Gastroenterology, Maillot Hospital, Algiers, Algeria 5Service of Oncology, Rouiba Hospital, Algiers, Algeria Correspondence should be addressed to Nadira Delhem; [email protected] and Chafia Touil-Boukoffa; [email protected] Received 5 November 2016; Revised 5 January 2017; Accepted 19 February 2017; Published 20 March 2017 Academic Editor: Kumar S. Bishnupuri Copyright © 2017 Hayet Rafa et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Colitis associated cancer (CAC) is the colorectal cancer (CRC) subtype that is associated with bowel disease such as ulcerative colitis (UC).ThedataonroleofNF-B signaling in development and progression of CAC were derived from preclinical studies, whereas data from human are rare. The aim of this work was to study the contribution of NF-BpathwayduringUCandCAC,aswellas the immunomodulatory effect of all-trans retinoic acid (AtRA). We analyzed the expression of NOS2,TNF- ,TLR4,andNF-B, in colonic mucosa. We also studied NO/TNF- modulation by LPS in colonic mucosa pretreated with AtRA. A marked increase in TLR4, NF-B, TNF-, and NOS2 expression was reported in colonic mucosa. The relationship between LPS/TLR4 and TNF-/NO production, as well as the role of NF-B signaling, was confirmed by ex vivo experiments and the role of LPS/TLR4 in NOS2/TNF- induction through NF-B pathway was suggested. AtRA downregulates NOS2 and TNF- expression. Collectively, our study indicates that AtRA modulates in situ LPS/TLR4/NF-B signaling pathway targeting NOS2 and TNF- expression. Therefore, we suggest that AtRA has a potential value in new strategies to improve the current therapy, as well as in the clinical prevention of CAC development and progression. 1. Introduction moderate-to-heavy alcohol use also increase the risk for CRC [4–6]. Several reports have shown that chronic inflammation Colorectal cancer (CRC) is one of the most common lethal predisposes individuals to various types of cancer [3, 7, 8]. cancers worldwide [1]. There are two major types of CRC, The risk of colorectal cancer is increased in patients with sporadic colorectal carcinoma (SCC) and colitis associated inflammatory bowel disease, particularly in long-standing cancer (CAC) [2]. Factors that may increase the risk of and extensive ulcerative colitis (UC) [8]. Then, colitis associ- colorectal cancer have been extensively studied [3, 4]. Phys- ated cancer (CAC) is the CRC subtype that is associated with ical inactivity, obesity, smoking, and dietary patterns such bowel disease (Crohn’s disease (CD) and ulcerative colitis as high red and processed meat consumption as well as (UC)) [9]. Both diseases are characterized by the immune 2 Mediators of Inflammation dysregulation in the intestine, involving a wide range of chronic diseases and cancers [29–32]. Retinoids are currently molecules leading to a chronically inflamed environment used as chemotherapies against cancers of epithelial origin [10–12]. [33]. All-trans retinoic acid (AtRA) is an active metabolite Although many reports have documented the critical link of retinoid and regulates a wide range of biologic processes between inflammation and development of colon cancer, our through the action of two families of nuclear retinoid recep- knowledge of the underlying mechanisms remains incom- tors, retinoid acid receptor (RAR) and retinoid X receptor plete. Different TLR ligands have been implicated in various (RXR). Heterodimers composed of an RAR and an RXR bind experimental tumor models and are known to play different to specific RA response elements (RAREs) in target genes roles. While some TLRs contribute to antitumor responses, [34, 35]. others conversely promote tumor growth and facilitate the AtRA has been shown to exert immunomodulatory and evasion of immune surveillance [13]. TLR4 signaling plays anti-inflammatory functions in various cell types [36–38]. In a crucial role in the generation of innate response but also our previous studies, we reported that AtRA inhibited the NO serves to activate the adaptive immune system in response production in proinflammatory cytokines stimulated periph- to cancer [13, 14]. Activation of TLR4 by Gram-negative eral blood mononuclear cells (PBMC) and monocytes from lipopolysaccharide (LPS) leads to the NF-Bactivationin IBD and Alzheimer disease patients [11, 39]. Furthermore, the intestinal mucosa [15] and induced the expression of retinoids are known to affect signaling pathways frequently many proinflammatory molecules including cytokines and altered which result in the development and progression of adhesion molecules [16, 17]. Among these cytokines, tumor CRC [32]. In this sense, understanding the pathway involved necrosis factor-alpha (TNF-) can further enhance NF- in cancer-related inflammation and targeting transcription B activation in various cell types [18]. TNF- is a mul- factorssuchasNF-B has attracted our attention. In this way, tifunctional cytokine involved in apoptosis, cell survival, we investigate the contribution of TLR4/NF-Bpathwayin inflammation, and immunity acting via two receptors (TNF UC and CAC Algerian patients, as well as the effect of AtRA receptor p55 or TNF-Rp75) [19, 20]. on TNF- and NOS2 expression. Proinflammatory mediators and cytokines such as nitric oxide (NO) and TNF- play important roles in regulating 2. Patients and Methods inflammatory response. Generation and secretion of a high NO concentration by infiltrating cells and resident activated 2.1. Patients. Thirty-five Algerian patients with ulcerative macrophages may lead to perpetuation of local tissue damage colitis, UC (14 men and 16 women; mean age 39.75 ± [21, 22]. The inducible NOS (iNOS) is expressed following 9.23 years; range 22–53 years), and 9 patients with colitis stimulation with lipopolysaccharide and/or inflammatory associated cancer, CAC (3 men and 6 women; mean age cytokinessuchasTNF- [22–24]. The activation of iNOS 55.88 ± 6.66 years; range 48–67 years), were enrolled in this leads to prolonged production of NO in high, potentially study. UC and CAC patients were diagnosed by standard cytotoxic concentrations [25]. In our previous studies, we endoscopic and histological examination in the Department reported that chronic UC is characterized by overexpression of Gastroenterology, Maillot Hospital, Algiers, Algeria, Ser- of iNOS with high levels of NO generation by PBMC vice of Oncology, Public hospital Rouiba Algiers Algeria and colonic mucosa stimulated with IFN- or IL-17A and and Anatomic Pathology service, Mustapha Pacha Algiers correlates with histological damage [10, 11]. Thus iNOS Algeria. generatedNOmaygivethecelladoublehitbybothdamaging The histopathological examination confirmed the diag- the DNA and inhibiting its repair processes. This effect of nosisofUCactivestageandcancer.Healthycontrols(= NO and its by-products may make NO one of the pivotal 16) were obtained from adult volunteer donors. Each patient mediators linking inflammation to carcinogenesis [25]. These has given a written

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