Multicentric Castleman disease (MCD) is

ObjectiveTo investigate whether interleukin‐6 (IL‐6) is a regulator of vascular endothelial growth factor (VEGF) in rheumatoid arthritis (RA).MethodsSerum VEGF levels in RA patients were assayed before and after 8 weeks or 24 weeks of maintenance therapy with humanized anti–IL‐6 receptor monoclonal antibody (anti–IL‐6R mAb). VEGF secreted by RA synovial fibroblasts cultured in the presence of IL‐6, IL‐1β, and/or tumor necrosis factor α (TNFα) was measured. The inhibitory effect of anti–IL‐6R mAb, recombinant IL‐1 receptor antagonist (IL‐1Ra), and anti‐TNFα mAb on VEGF production was also examined.ResultsSerum VEGF levels in RA patients before anti–IL‐6R mAb therapy were significantly higher than those in healthy controls (P < 0.0005). Treatment of RA patients with anti–IL‐6R mAb normalized serum VEGF levels. In the in vitro study, IL‐6 and IL‐1β each induced a slight amount of VEGF production in synovial cells, but TNFα did not. Although VEGF‐inducing activity of these cytokines was not remarkable when they were added alone, IL‐6 acted synergistically with IL‐1β or TNFα to induce VEGF production. There was no synergistic effect between IL‐1β and TNFα. In the presence of all of these cytokines, anti–IL‐6R mAb eliminated the synergistic effect of IL‐6, IL‐1β, and TNFα, while IL‐1Ra or anti‐TNFα mAb did not.ConclusionAnti–IL‐6R mAb therapy reduced VEGF production in RA. IL‐6 is the pivotal cytokine that induces VEGF production in synergy with IL‐1β or TNFα, and this may be the mechanism by which IL‐6 blockade effectively suppresses VEGF production in synovial fibroblasts.

The prevalence of allergic diseases has increased all over the world during the last two decades. Dietary change is considered to be one of the environmental factors that cause this increase and worsen allergic symptoms. If this is the case, an appropriate intake of foods or beverages with anti-allergic activities is expected to prevent the onset of allergic diseases and ameliorate allergic symptoms. Flavonoids, ubiquitously present in vegetables, fruits or teas possess anti-allergic activities. Flavonoids inhibit histamine release, synthesis of IL-4 and IL-13 and CD40 ligand expression by basophils. Analyses of structure-activity relationships of 45 flavones, flavonols and their related compounds showed that luteolin, ayanin, apigenin and fisetin were the strongest inhibitors of IL-4 production with an IC(50) value of 2-5 microM and determined a fundamental structure for the inhibitory activity. The inhibitory activity of flavonoids on IL-4 and CD40 ligand expression was possibly mediated through their inhibitory action on activation of nuclear factors of activated T cells and AP-1. Administration of flavonoids into atopic dermatitis-prone mice showed a preventative and ameliorative effect. Recent epidemiological studies reported that a low incidence of asthma was significantly observed in a population with a high intake of flavonoids. Thus, this evidence will be helpful for the development of low molecular compounds for allergic diseases and it is expected that a dietary menu including an appropriate intake of flavonoids may provide a form of complementary and alternative medicine and a preventative strategy for allergic diseases. Clinical studies to verify these points are now in progress.

Serum amyloid A (SAA) is a sensitive marker of acute-phase responses and known as a precursor protein of amyloid fibril in amyloid A (AA) (secondary) amyloidosis. Since the serum SAA level is also closely related to activity of chronic inflammatory disease and coronary artery disease, it is important to clarify the exact induction mechanism of SAA from the clinical point of view. Here we provide evidence that STAT3 plays an essential role in cytokine-driven SAA expression, although the human SAA gene shows no typical STAT3 response element (RE) in its promoters. STAT3 and nuclear factor κ κ κ κB (NF-κ κ κ κB) p65 first form a complex following interleukin (IL)-1 and IL-6 (IL-1+6) stimulation, after which STAT3 interacts with nonconsensus sequences at a 3′ ′ ′ ′ site of the SAA gene promoter's NF-κ κ κ κB RE. Moreover, co-expression of p300 with STAT3 dramatically enhances the transcriptional activity of SAA. The formation of a complex with STAT3, NF-κ κ κ κB p65, and p300 is thus essential for the synergistic induction of the SAA gene by IL-1+6 stimulation. Our findings are expected to aid the understanding of the inflammatory status of AA amyloidosis to aid development of a therapeutic strategy for this disease by means of normalization of serum SAA levels.

No abstract

Objective. SSc is an autoimmune disease characterized by fibrosis of the skin and internal organs. Although the aetiology remains uncertain, many reports have suggested that IL-6 is involved in SSc pathogenesis. Tocilizumab, an anti-IL-6 receptor antibody, is an anti-arthritis medicine that works through the blockade of IL-6 functions. To examine the effect of tocilizumab on SSc, we administered tocilizumab to two SSc patients.Methods. Two dcSSc patients were administered tocilizumab at 8 mg/kg once a month for 6 months. One patient had pulmonary fibrosis assessed by CT and spirometry, and the other had chronic renal failure caused by scleroderma renal crisis. Their skin condition was monitored with a Vesmeter and the modified Rodnan total skin score (mRTSS). Skin biopsies were obtained before and after the tocilizumab treatment to investigate the histological changes.Results. After tocilizumab treatment, both patients showed softening of the skin with reductions of 50.7 and 55.7% in the total z-score of Vesmeter hardness and 51.9 and 23.0% in the mRTSS, respectively. Histological examination showed thinning of the collagen fibre bundles in the dermis. The creatinine clearance in the patient with chronic renal failure improved from 38 to 55 ml/min. However, the fibrotic changes in the lung in the other patient remained unchanged.Conclusions. In the two cases of SSc that we report here, softening of the skin was observed during the treatment with tocilizumab.

C-reactive protein (CRP) is a sensitive marker and mediator of inflammation, whereas IL-6 blocking therapy can normalize serum levels of CRP in chronic inflammatory diseases. We investigated the precise synergistic induction mechanism of CRP gene expression by IL-1 and IL-6 in Hep3B cells. In the early induction phase, IL-1 inhibited IL-6-mediated CRP gene expression, and NF-κB p65 inhibited the luciferase activity of pGL3-CRP by IL-1 plus IL-6 even in the presence of overexpressed STAT3. In the late induction phase, we focused on JNK and p38 activated by IL-1. SP600125 reduced the expression of the CRP gene induced by IL-1 plus IL-6. Unexpectedly, overexpression of c-Fos dramatically enhanced the luciferase activity by IL-1 and IL-6 even though the CRP gene has no AP-1 response element (RE) in its promoter. The augmentative effect of c-Fos required the presence of STAT3 and 3′-hepatocyte NF-1 (HNF-1) RE, which were eliminated by dominant negative STAT3 and HNF-1α, respectively. SB203580 inhibited the phosphorylation of c-Fos enhanced by IL-1 plus IL-6, and diminished expression of the CRP gene. Immunoprecipitation, Western blot analysis, the Supershift assay using a CRP oligonucleotide containing STAT3 and 3′-HNF-1 RE, and the chromatin immunoprecipitation assay demonstrated that c-Fos/STAT3/HNF-1α forms a complex on the CRP gene promoter. Because human fetus liver cells failed to express c-Fos/STAT3/HNF-1α showed no CRP production, transcriptional complex formation of c-Fos/STAT3/HNF-1α is essential for the synergistic induction of CRP gene expression by IL-1 plus IL-6. Our findings fully explain the clinical results of IL-6 blocking therapy and are expected to contribute to the development of a therapeutic strategy for chronic inflammatory diseases.

No abstract