title: Increased interleukin-17 production via a phosphoinositide 3-kinase/Akt and nuclear factor kappaB-dependent pathway in patients with rheumatoid arthritis.
abstract: Inflammatory mediators have been recognized as being important in the pathogenesis of rheumatoid arthritis (RA). Interleukin (IL)-17 is an important regulator of immune and inflammatory responses, including the induction of proinflammatory cytokines and osteoclastic bone resorption. Evidence for the expression and proinflammatory activity of IL-17 has been demonstrated in RA synovium and in animal models of RA. Although some cytokines (IL-15 and IL-23) have been reported to regulate IL-17 production, the intracellular signaling pathways that regulate IL-17 production remain unknown. In the present study, we investigated the role of the phosphoinositide 3-kinase (PI3K)/Akt pathway in the regulation of IL-17 production in RA. Peripheral blood mononuclear cells (PBMC) from patients with RA (n = 24) were separated, then stimulated with various agents including anti-CD3, anti-CD28, phytohemagglutinin (PHA) and several inflammatory cytokines and chemokines. IL-17 levels were determined by sandwich enzyme-linked immunosorbent assay and reverse transcription-polymerase chain reaction. The production of IL-17 was significantly increased in cells treated with anti-CD3 antibody with or without anti-CD28 and PHA (P < 0.05). Among tested cytokines and chemokines, IL-15, monocyte chemoattractant protein-1 and IL-6 upregulated IL-17 production (P < 0.05), whereas tumor necrosis factor-alpha, IL-1beta, IL-18 or transforming growth factor-beta did not. IL-17 was also detected in the PBMC of patients with osteoarthritis, but their expression levels were much lower than those of RA PBMC. Anti-CD3 antibody activated the PI3K/Akt pathway; activation of this pathway resulted in a pronounced augmentation of nuclear factor kappaB (NF-kappaB) DNA-binding activity. IL-17 production by activated RA PBMC is completely or partly blocked in the presence of the NF-kappaB inhibitor pyrrolidine dithiocarbamate and the PI3K/Akt inhibitor wortmannin and LY294002, respectively. However, inhibition of activator protein-1 and extracellular signal-regulated kinase 1/2 did not affect IL-17 production. These results suggest that signal transduction pathways dependent on PI3K/Akt and NF-kappaB are involved in the overproduction of the key inflammatory cytokine IL-17 in RA.
authors.affiliation: Department of Medicine, Division of Rheumatology, The Center for Rheumatic Diseases, and The Rheumatism Research Center (RhRC), Catholic Research Institutes of Medical Sciences, Catholic University of Korea, Seoul, Korea. woon1212@catholic.ac.kr
authors.forename: Kyoung-Woon
authors.initials: KW
authors.lastname: Kim
authors.forename: Mi-La
authors.initials: ML
authors.lastname: Cho
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Park
authors.forename: Chong-Hyeon
authors.initials: CH
authors.lastname: Yoon
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Park
authors.forename: Sang-Heon
authors.initials: SH
authors.lastname: Lee
authors.forename: Ho-Youn
authors.initials: HY
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000730:Androstadienes / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D018925:Chemokines / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000502:physiology*; D010003:Osteoarthritis / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010835:Phytohemagglutinins / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D013859:Thiocarbamates / Q000494:pharmacology; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D017252:CD3 Complex; D018925:Chemokines; D002867:Chromones; D016207:Cytokines; D005419:Flavonoids; D007093:Imidazoles; D020381:Interleukin-17; D009025:Morpholines; D016328:NF-kappa B; D010835:Phytohemagglutinins; D011725:Pyridines; D011759:Pyrrolidines; D011994:Recombinant Proteins; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077191:Wortmannin