Kazuhiro Yokota

Combination of tumor necrosis factor α and interleukin-6 induces mouse osteoclast-like cells with bone resorption activity both in vitro and in vivo.

To clarify the function of osteoclast‐like multinuclear cells differentiated from bone marrow–derived macrophages (BMMs) by a combination of tumor necrosis factor α (TNFα) and interleukin‐6 (IL‐6), and to investigate the molecular mechanisms underlying the differentiation.

Aberrant histone acetylation contributes to elevated interleukin-6 production in rheumatoid arthritis synovial fibroblasts.

Accumulating evidence indicates that epigenetic aberrations have a role in the pathogenesis of rheumatoid arthritis (RA). However, reports on histone modifications are as yet quite limited in RA. Interleukin (IL)-6 is an inflammatory cytokine which is known to be involved in the pathogenesis of RA. Here we report the role of histone modifications in elevated IL-6 production in RA synovial fibroblasts (SFs). The level of histone H3 acetylation (H3ac) in the IL-6 promoter was significantly higher in RASFs than osteoarthritis (OA) SFs. This suggests that chromatin structure is in an open or loose state in the IL-6 promoter in RASFs. Furthermore, curcumin, a histone acetyltransferase (HAT) inhibitor, significantly reduced the level of H3ac in the IL-6 promoter, as well as IL-6 mRNA expression and IL-6 protein secretion by RASFs. Taken together, it is suggested that hyperacetylation of histone H3 in the IL-6 promoter induces the increase in IL-6 production by RASFs and thereby participates in the pathogenesis of RA.

Marked Induction of c-Maf Protein during Th17 Cell Differentiation and Its Implication in Memory Th Cell Development

Until recently, effector T helper (Th) cells have been classified into two subsets, Th1 and Th2 cells. Since the discovery of Th17 cells, which produce IL-17, much attention has been given to Th17 cells, mainly because they have been implicated in the pathogenesis of various inflammatory diseases. We have performed transcriptome analysis combined with factor analysis and revealed that the expression level of c-Maf, which is considered to be important for Th2 differentiation, increases significantly during the course of Th17 differentiation. The IL-23 receptor (IL-23R), which is important for Th17 cells, is among putative transcriptional targets of c-Maf. Interestingly, the analysis of c-Maf transgenic Th cells revealed that the overexpression of c-Maf did not lead to the acceleration of the early stage of Th17 differentiation but rather to the expansion of memory phenotype cells, particularly with Th1 and Th17 traits. Consistently, mouse wild-type memory Th cells expressed higher mRNA levels of c-Maf, IL-23R, IL-17, and IFN-γ than control cells; in contrast, Maf−/− memory Th cells expressed lower mRNA levels of those molecules. Thus, we propose that c-Maf is important for the development of memory Th cells, particularly memory Th17 cells and Th1 cells.

Histone Methylation and STAT‐3 Differentially Regulate Interleukin‐6–Induced Matrix Metalloproteinase Gene Activation in Rheumatoid Arthritis Synovial Fibroblasts

Synovial fibroblasts (SFs) produce matrix‐degrading enzymes that cause joint destruction in rheumatoid arthritis (RA). Epigenetic mechanisms play a pivotal role in autoimmune diseases. This study was undertaken to elucidate the epigenetic mechanism that regulates the transcription of matrix metalloproteinases (MMPs) in RASFs.

Analysis of cytokine production patterns of peripheral blood mononuclear cells from a rheumatoid arthritis patient successfully treated with rituximab

We had a rheumatoid arthritis (RA) patient resistant to multiple drugs and who developed panniculitis due to etanercept treatment, then responded fairly well to rituximab. Intracellular staining of cytokines in the peripheral blood mononuclear cells before and after rituximab administration revealed that the cytokine production, representative of T-helper (Th)1-, Th2-, and Th17-type responses, decreased abruptly after the treatment. Interestingly, this timing coincided with that of the manifestation of the beneficial effect. This relationship may provide useful insight into the mechanism of action of the drug and hence about the pathogenesis of RA.

Subcutaneous panniculitis-like T-cell lymphoma accompanied by Sjögren's syndrome.

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Vasculo-Behçet’s disease with non-traumatic subcapsular hematoma of the kidney and aneurysmal dilatations of the celiac and superior mesenteric arteries

We report a patient with vasculo-Behçet’s disease treated successfully with a high dose of prednisolone. In 2002, the patient was diagnosed with vasculo-Behçet’s disease. He was admitted to our hospital because of sudden-onset right lower back pain in June 2006. Upon admission, abdominal angiography revealed aneurysmal dilatations of the celiac and superior mesenteric arteries. He was treated promptly with high-dose prednisolone, after which the aneurysms displayed no further enlargement. As we believe this case to be quite rare, we report this case with a literature review in support of this characterization.

Detection of synovial inflammation in rheumatic diseases using superb microvascular imaging: Comparison with conventional power Doppler imaging

Abstract Aim: Superb microvascular imaging (SMI), a novel ultrasonography, is based on the sensitivity of Doppler technology. This study evaluated power Doppler (PD) ultrasound signals in patients with rheumatic disease using SMI and conventional PD imaging (cPDI) and compared the correlations of these signals to clinical assessments. Methods: Thirty-nine patients with rheumatic disease (27 rheumatoid arthritis [RA] and 12 non-RA) were enrolled. We investigated SMI and cPDI signals in 26 joints using an Aplio 300. Individual scores were summed to calculate total SMI and cPDI scores. Results: Total SMI scores were significantly higher than total cPDI scores in patients with RA, but not in those with the non-RA disease. Total SMI score was associated with serum levels of C-reactive protein (CRP) and matrix metalloproteinase-3; disease activity score 28-CRP and health assessment questionnaire disability index scores, and SMI were more sensitive to detect active synovitis than cPDI in RA patients. Among the joint regions, the wrists and metacarpophalangeal joints were more sensitive to the detection of synovial inflammation using SMI in patients with RA. Conclusion: SMI was more sensitive in detecting synovial inflammation than cPDI in patients with RA. SMI could be a potentially useful imaging modality for accurately diagnosing and monitoring the disease activity of RA.

A significant induction of neutrophilic chemoattractants but not RANKL in synoviocytes stimulated with interleukin 17

Interleukin 17 (IL-17) is a cytokine implicated in the promotion of osteoclastogenesis. Its effect has been believed not to be directly exerted on osteoclast precursors, but rather indirectly carried out via an induction of receptor activator of NF-κB ligand (RANKL), the osteoclast differentiation factor, on osteoclast-supporting cells, which in turn exert an effect on osteoclast precursors. The mechanistic details, however, remain unclear. In this study, we first performed a transcriptome analysis of synoviocytes derived from a patient with rheumatoid arthritis cultured in the presence or absence of IL-17. We discovered that most of the genes significantly induced by IL-17 were chemokines with a chemotactic effect on neutrophils. We confirmed these results by quantitative RT-PCR and ELISA. Unexpectedly, the stimulation with IL-17 alone did not induce the expression of RANKL either at the mRNA or the protein level. The induction of RANKL was observed when IL-17 was added in combination with 1,25-dihydroxyvitamin D3 and prostaglandin E2, well-known inducers of RANKL, although the exact mechanism of this synergistic effect remains unclear. IL-6 and monocyte chemoattractant protein-1 were also significantly induced by IL-17 at both the mRNA and protein levels. Thus, it appears that IL-17 induces the migration of neutrophils and monocytes/macrophages through the activation of synoviocytes, and enhances a positive feedback loop composed of proinflammatory cytokines IL-6 and IL-17.

Histone methylation and STAT3 differentially regulate IL‐6‐induced MMP gene activation in rheumatoid arthritis synovial fibroblasts

Synovial fibroblasts (SFs) produce matrix‐degrading enzymes that cause joint destruction in rheumatoid arthritis (RA). Epigenetic mechanisms play a pivotal role in autoimmune diseases. This study was undertaken to elucidate the epigenetic mechanism that regulates the transcription of matrix metalloproteinases (MMPs) in RASFs.