Exp Mol Med.  2011 Aug;43(8):446-454. 10.3858/emm.2011.43.8.050.

Myeloid differentiation primary response protein 88 blockade upregulates indoleamine 2,3-dioxygenase expression in rheumatoid synovial fibroblasts

• Park MK
• Oh HJ
• Heo YM
• Park EM
• Cho ML
• Kim HY
• Park SH

• KMID: 1022119
• DOI: http://doi.org/10.3858/emm.2011.43.8.050

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 siRNA-mediated knockdown of MyD88.

Keyword

indoleamine-pyrrole 2,3,-dioxygenase; myeloid differentiation factor 88; rheumatoid arthritis; TICAM1 protein, human; toll-like receptors

MeSH Terms

Adaptor Proteins, Vesicular Transport/genetics/metabolism
Arthritis, Rheumatoid/*metabolism
Blotting, Western
Cells, Cultured
Fibroblasts/drug effects/*metabolism
Humans
Immunohistochemistry
Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics/*metabolism
Interleukin-12/pharmacology
Interleukin-16/pharmacology
Interleukin-17/pharmacology
Interleukin-23/pharmacology
Lipopolysaccharides/pharmacology
Myeloid Differentiation Factor 88/genetics/*metabolism
Poly I-C/pharmacology
Polymerase Chain Reaction
RNA, Small Interfering/genetics/physiology
Synovial Membrane/*cytology
Toll-Like Receptor 4/genetics/metabolism
Tumor Necrosis Factor-alpha/pharmacology