title: Myeloid differentiation primary response protein 88 blockade upregulates indoleamine 2,3-dioxygenase expression in rheumatoid synovial fibroblasts.
abstract: Indoleamine 2,3-dioxygenase (IDO) is a key negative regulator of immune responses and has been implicated in tumor tolerance, autoimmune disease and asthma. IDO was detected in the joint synovial tissue in the inflammatory microenvironment of rheumatoid arthritis (RA), but IDO expression in joint synovial tissue is not sufficient to overcome the inflamed synovial environment. This study aimed to unravel the mechanisms involving the failure to activate tolerogenic IDO in the inflamed joint. We demonstrate that both poly (I:C) and lipopolysaccharide (LPS) induce expression of IDO in synovial fibroblasts. However, inflammatory cytokines such as IL-17, TNF-alpha, IL-12, IL-23 and IL-16 did not induce IDO expression. Poly (I:C) appeared to induce higher IDO expression than did LPS. Surprisingly, toll-like receptor (TLR)4-mediated IDO expression was upregulated after depletion of myeloid differentiation primary response protein 88 (MyD88) in synovial fibroblasts using small interfering RNA (siRNA). IDO, TLR3 and TLR4 were highly expressed in synovial tissue of RA patients compared with that of osteoarthritis patients. In addition, RA patients with severe disease activity had higher levels of expression of IDO, TLR3 and TLR4 in the synovium than patients with mild disease activity. These data suggest that upregulation of IDO expression in synovial fibroblasts involves TLR3 and TLR4 activation by microbial constituents. We showed that the mechanisms responsible for IDO regulation primarily involve MyD88 signaling in synovial fibroblasts, as demonstrated by siRNAmediated knockdown of MyD88.
authors.affiliation: The Rheumatism Research, Center Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 137-040, Korea.
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Park
authors.forename: Hye-Jwa
authors.initials: HJ
authors.lastname: Oh
authors.forename: Yang-Mi
authors.initials: YM
authors.lastname: Heo
authors.forename: Eun-Mi
authors.initials: EM
authors.lastname: Park
authors.forename: Mi-La
authors.initials: ML
authors.lastname: Cho
authors.forename: Ho-Youn
authors.initials: HY
authors.lastname: Kim
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Park
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D018664:Interleukin-12 / Q000494:pharmacology; D019410:Interleukin-16 / Q000494:pharmacology; D020381:Interleukin-17 / Q000494:pharmacology; D053759:Interleukin-23 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D011070:Poly I-C / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering / Q000235:genetics / Q000502:physiology; D013583:Synovial Membrane / Q000166:cytology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D019410:Interleukin-16; D020381:Interleukin-17; D053759:Interleukin-23; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D034741:RNA, Small Interfering; C470409:TICAM1 protein, human; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D011070:Poly I-C