Abstract
Recent studies have demonstrated that the complement system participates in the regulation of T cell functions. To address the local biosynthesis of complement components in inflammatory bowel disease (IBD) mucosa, we investigated C3 and interleukin (IL)-17 mRNA expression in mucosal samples obtained from patients with IBD. The molecular mechanisms underlying C3 induction were investigated in human colonic subepithelial myofibroblasts (SEMFs). IL-17 and C3 mRNA expressions in the IBD mucosa were evaluated by real-time polymerase chain reaction. The C3 levels in the supernatant were determined by enzyme-linked immunosorbent assay. IL-17 and C3 mRNA expressions were elevated significantly in the active lesions from ulcerative colitis (UC) and Crohn's disease (CD) patients. There was a significant positive correlation between IL-17 and C3 mRNA expression in the IBD mucosa. IL-17 stimulated a dose- and time-dependent increase in C3 mRNA expression and C3 secretion in colonic SEMFs. The C3 molecules secreted by colonic SEMFs were a 115-kDa alpha-chain linked to a 70-kDa beta-chain by disulphide bonds, which was identical to serum C3. The IL-17-induced C3 mRNA expression was blocked by p42/44 mitogen-activated protein kinase (MAPK) inhibitors (PD98059 and U0216) and a p38 MAPK inhibitor (SB203580). Furthermore, IL-17-induced C3 mRNA expression was inhibited by an adenovirus containing a stable mutant form of I kappaB alpha. C3 and IL-17 mRNA expressions are enhanced, with a strong correlation, in the inflamed mucosa of IBD patients. Part of these clinical findings was considered to be mediated by the colonic SEMF response to IL-17.
MeSH terms
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Adenoviridae
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Colitis, Ulcerative / genetics
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Colitis, Ulcerative / immunology*
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Colitis, Ulcerative / metabolism
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Colitis, Ulcerative / pathology
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Colon / immunology
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Colon / metabolism
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Colon / pathology
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Complement C3 / biosynthesis
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Complement C3 / genetics
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Complement C3 / immunology*
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Crohn Disease / genetics
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Crohn Disease / immunology*
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Crohn Disease / metabolism
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Crohn Disease / pathology
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Female
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Flavonoids
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Gene Expression Regulation / immunology*
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Humans
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I-kappa B Proteins / genetics
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I-kappa B Proteins / immunology
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I-kappa B Proteins / metabolism
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Imidazoles / pharmacology
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Interleukin-17 / biosynthesis
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Interleukin-17 / genetics
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Interleukin-17 / immunology*
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Interleukin-17 / pharmacology
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Intestinal Mucosa / immunology*
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Intestinal Mucosa / metabolism
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Intestinal Mucosa / pathology
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Male
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / immunology
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mutation
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NF-KappaB Inhibitor alpha
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Pyridines / pharmacology
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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RNA, Messenger / immunology*
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Reverse Transcriptase Polymerase Chain Reaction / methods
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Time Factors
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Transduction, Genetic
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / immunology
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Complement C3
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Enzyme Inhibitors
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Flavonoids
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I-kappa B Proteins
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Imidazoles
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Interleukin-17
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NFKBIA protein, human
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Pyridines
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RNA, Messenger
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NF-KappaB Inhibitor alpha
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Mitogen-Activated Protein Kinase 1
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p38 Mitogen-Activated Protein Kinases
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SB 203580
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one