All-Trans Retinoic Acid Modulates TLR4/NF- κ B Signaling Pathway Targeting TNF- α 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 , Houria Saoula (3) , Said Belhadef (4) , Mourad Belkhelfa (1) , Aziza Boukercha (1) , Ryma Toumi (1) , Imene Soufli (1) , Olivier Morales (2) , Yvan de Launoit (5) , Hassen Mahfouf (4) , M'Hamed Nakmouche (3) , Nadira Delhem (2) , Chafia Touil-Boukoffa (1)

1 USTHB - Université des Sciences et de la Technologie Houari Boumediene = University of Sciences and Technology Houari Boumediene [Alger]
2 IBLI - Institut de biologie de Lille - IBL
3 Hôpital Maillot [Algérie]
4 Hôpital Rouïba [Algerie]
5 M3T - Mécanismes de la Tumorigénèse et Thérapies Ciblées - UMR 8161

Colitis associated cancer (CAC) is the colorectal cancer (CRC) subtype that is associated with bowel disease such as ulcerative colitis (UC). The data on role of NF-κB 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-κB pathway during UC and CAC, as well as the immunomodulatory effect of all-trans retinoic acid (AtRA). We analyzed the expression of NOS2, TNF-α, TLR4, and NF-κB, in colonic mucosa. We also studied NO/TNF-α modulation by LPS in colonic mucosa pretreated with AtRA. A marked increase in TLR4, NF-κB, TNF-α, and NOS2 expression was reported in colonic mucosa. The relationship between LPS/TLR4 and TNF-α/NO production, as well as the role of NF-κB signaling, was confirmed by ex vivo experiments and the role of LPS/TLR4 in NOS2/TNF-α induction through NF-κB pathway was suggested. AtRA downregulates NOS2 and TNF-α expression. Collectively, our study indicates that AtRA modulates in situ LPS/TLR4/NF-κB signaling pathway targeting NOS2 and TNF-α 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.

Domaines: Génomique, Transcriptomique et Protéomique [q-bio.GN]; Hépatologie et Gastroentérologie; Cancer

Hayet Rafa, Sarra Benkhelifa, Sonia Aityounes, Houria Saoula, Said Belhadef, et al.. All-Trans Retinoic Acid Modulates TLR4/NF- κ B Signaling Pathway Targeting TNF- α and Nitric Oxide Synthase 2 Expression in Colonic Mucosa during Ulcerative Colitis and Colitis Associated Cancer. Mediators of Inflammation, 2017, 2017, pp.7353252. ⟨10.1155/2017/7353252⟩. ⟨hal-02391613⟩