title: IL-23/IL-17A axis correlates with the nitric oxide pathway in inflammatory bowel disease: immunomodulatory effect of retinoic acid.
abstract: Inflammatory bowel diseases (IBDs) are chronic inflammatory diseases of the gastrointestinal tract, which are clinically present as 1 of the 2 disorders, Crohn's disease (CD) or ulcerative colitis (UC) (Rogler 2004). The immune dysregulation in the intestine plays a critical role in the pathogenesis of IBD, involving a wide range of molecules, including cytokines. The aim of this work was to study the involvement of T-helper 17 (Th17) subset in the bowel disease pathogenesis by the nitric oxide (NO) pathway in Algerian patients with IBD. We investigated the correlation between the proinflammatory cytokines [(interleukin (IL)-17, IL-23, and IL-6] and NO production in 2 groups of patients. We analyzed the expression of messenger RNAs (mRNAs) encoding Th17 cytokines, cytokine receptors, and NO synthase 2 (NOS2) in plasma of the patients. In the same way, the expression of p-signal transducer and activator of transcription 3 (STAT3) and NOS2 was measured by immunofluorescence and immunohistochemistry. We also studied NO modulation by proinflammatory cytokines (IL-17A, IL-6, tumor necrosis factor α, or IL-1β) in the presence or absence of all-trans retinoic acid (At RA) in peripheral blood mononuclear cells (PBMCs), monocytes, and in colonic mucosa cultures. Analysis of cytokines, cytokine receptors, and NOS2 transcripts revealed that the levels of mRNA transcripts of the indicated genes are elevated in all IBD groups. Our study shows a significant positive correlation between the NO and IL-17A, IL-23, and IL-6 levels in plasma of the patients with IBD. Interestingly, the correlation is significantly higher in patients with active CD. Our study shows that both p-STAT3 and inducible NOS expression was upregulated in PBMCs and colonic mucosa, especially in patients with active CD. At RA downregulates NO production in the presence of proinflammatory cytokines for the 2 groups of patients. Collectively, our study indicates that the IL-23/IL-17A axis plays a pivotal role in IBD pathogenesis through the NO pathway.
authors.affiliation: Team: Cytokines and NO Synthases, Laboratory of Cellular and Molecular Biology (LBCM), Faculty of Biological Science, USTHB, Algiers, Algeria.
authors.forename: Hayet
authors.initials: H
authors.lastname: Rafa
authors.forename: Houria
authors.initials: H
authors.lastname: Saoula
authors.forename: Mourad
authors.initials: M
authors.lastname: Belkhelfa
authors.forename: Oussama
authors.initials: O
authors.lastname: Medjeber
authors.forename: Imene
authors.initials: I
authors.lastname: Soufli
authors.forename: Ryma
authors.initials: R
authors.lastname: Toumi
authors.forename: Yvan
authors.initials: Y
authors.lastname: de Launoit
authors.forename: Olivier
authors.initials: O
authors.lastname: Moralès
authors.forename: M'hamed
authors.initials: M
authors.lastname: Nakmouche
authors.forename: Nadira
authors.initials: N
authors.lastname: Delhem
authors.forename: Chafia
authors.initials: C
authors.lastname: Touil-Boukoffa
mesh_terms: D000328:Adult; D000462:Algeria; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D056747:Immunomodulation; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000276:immunology; D020381:Interleukin-17 / Q000097:blood / Q000378:metabolism*; D053759:Interleukin-23 / Q000097:blood / Q000378:metabolism*; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology; D014212:Tretinoin / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D020381:Interleukin-17; D053759:Interleukin-23; D015850:Interleukin-6; D018121:Receptors, Cytokine; D050796:STAT3 Transcription Factor; D009569:Nitric Oxide; D014212:Tretinoin; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II