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

The Rheumatism Research, Center Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 137-040, Korea.
Experimental and Molecular Medicine (Impact Factor: 3.45). 06/2011; 43(8):446-54. DOI: 10.3858/emm.2011.43.8.050
Source: PubMed


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.

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Available from: Eun-Mi Park, Apr 23, 2015
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    • "Indoleamine 2,3dioxgenase (IDO) is a catabolic enzyme which mediates tryptophan degradation [11]. It is widely expressed in various cells including tumor cells [12], dendritic cells [13], macrophages [14], microglia [15], eosinophils [16], fibroblasts [17], and endothelial cells [18]. IDO expression is known to be induced by various stimuli including cytokines such as IFN-γ, pathogen-associated molecular patterns and co-stimulatory molecules [19]. "
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    ABSTRACT: C57BL/6 mice are known to be resistant to the development of collagen-induced arthritis (CIA). However, they show a severe arthritic phenotype when the Ifng gene is deleted. Although it has been proposed that IFN-γ suppresses inflammation in CIA via suppressing Th17 which is involved in the pathogenesis of CIA, the exact molecular mechanism of the Th17 regulation by IFN-γ is poorly understood. This study was conducted to 1) clarify that arthritogenic condition of IFN-γ knockout (KO) mice is dependent on the disinhibition of Th17 and 2) demonstrate that IFN-γ-induced indoleamine2,3dioxgenase (IDO) is engaged in the regulation of Th17. The results showed that the IFN-γ KO mice displayed increased levels of IL-17 producing T cells and the exacerbation of arthritis. Also, production of IL-17 by the splenocytes of the IFN-γ KO mice was increased when cultured with type II collagen. When Il17 was deleted from the IFN-γ KO mice, only mild arthritis developed without any progression of the arthritis score. The proportion of CD44(high)CD62L(low) memory-like T cells were elevated in the spleen, draining lymph node and mesenteric lymph node of IFN-γ KO CIA mice. Meanwhile, CD44(low)CD62L(high) naïve T cells were increased in IFN-γ and IL-17 double KO CIA mice. When Th17 polarized CD4+ T cells of IFN-γ KO mice were co-cultured with their own antigen presenting cells (APCs), a greater increase in IL-17 production was observed than in co-culture of the cells from wild type mice. In contrast, when APCs from IFN-γ KO mice were pretreated with IFN-γ, there was a significant reduction in IL-17 in the co-culture system. Of note, pretreatment of 1-methyl-DL- tryptophan, a specific inhibitor of IDO, abolished the inhibitory effects of IFN-γ. Given that IFN-γ is a potent inducer of IDO in APCs, these results suggest that IDO is involved in the regulation of IL-17 by IFN-γ.
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    ABSTRACT: The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) finely regulates both innate and adaptive immune responses through the degradation of the essential amino acid tryptophan into kynurenine and other downstream metabolites, which suppress effector T-cell function and promote the differentiation of regulatory T cells. A novel role for IDO1 as a signaling molecule and a modifier of innate inflammatory responses is now emerging. In particular, IDO1 can either support or antagonize inflammation in a context- and tissue-dependent manner. Studies in experimental arthritis have unravelled a previously unappreciated role for IDO in controlling B-cell activation and autoantibody production. IDO dysregulation has been documented in patients with systemic lupus erythematosus, systemic sclerosis and Sjögren's syndrome, as well as in severe sepsis and chronic kidney disease. This article summarizes the contribution of IDO to the pathophysiology of inflammatory/autoimmune disorders, and discusses whether strategies to restore metabolic equilibrium in the kynurenine pathway might be pursued in diseases states such as rheumatoid arthritis and systemic sclerosis.
    Current Medicinal Chemistry 09/2012; 19(31). DOI:10.2174/092986712803833353 · 3.85 Impact Factor
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    ABSTRACT: The roles of Toll-like receptors (TLRs) and their myeloid differentiation response gene 88 (MyD88)-dependent and MyD88-independent signaling cascade particularly with regard to the pathogenesis and regulation of immune responses in idiopathic inflammatory myopathies are unclear. We investigated these pathways in muscle biopsies from 5 cases each of polymyositis, inclusion body myositis, dermatomyositis, vasculitis-associated interstitial myositis, and noninflammatory neurogenic atrophy. Toll-like receptor 2, TLR4, TLR9, and MyD88 mRNA transcripts and protein expression were increased in all subtypes of idiopathic inflammatory myopathies. Upregulation of MyD88 was associated with increased mRNA levels of interferon-γ, interleukin 12p40, and interleukin 17, suggesting NF-κB activation via the MyD88-dependent pathway in early stages. The costimulatory molecules CD80 and CD86 were expressed on inflammatory infiltrates in idiopathic inflammatory myopathies and may additionally contribute to activation of the MyD88-independent pathway, leading to nuclear factor-κB activation in late stages. Our data suggest that nuclear factor-κB activation via both the MyD88-dependent and the MyD88-independent pathways contributes to the proinflammatory milieu in idiopathic inflammatory myopathies.
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