Panax Notoginseng Saponin Controls IL-17 Expression in Helper T Cells.

PURPOSE: Panax Notoginseng, a traditional Chinese medicine, is known as an anti-inflammatory herb. However, the molecular mechanism by which it controls helper T cell mediated immune responses is largely unknown. METHODS: Naive CD4+ T cells isolated from healthy donors, patients with Behcet's disease, and C57BL/6 mice were polarized into Th1, Th17, and Treg cells. Proliferation and cytokine expression were measured in these cells with the presence or absence of Panax Notoginseng saponins (PNS). Genomewide expression profiles of Th1, Th17, and Treg cells were assessed using Affymetrix microarray analysis. RESULTS: We found that PNS control the proliferation and differentiation of Th17 cells by globally downregulating the expression of inflammatory cytokines and cell cycle genes. CONCLUSIONS: These findings demonstrated that PNS function as an anti-inflammatory agent through directly targeting Th17 cell mediated immune response.

Berberine exerts an anti-inflammatory role in ocular Behcet's disease.

Behcet's disease is a multi­system inflammatory disorder, and ocular Behcet's disease (OBD) is one of the most common causes of uveitis in China. A number of studies have indicated that Th17 cells, a subset of interleukin-17 (IL-17)-producing CD4+ T­helper cells, serve important roles in the pathogenesis of OBD. Berberine (BBR) is an isoquinoline derivative alkaloid isolated from Chinese herbs, and has been used traditionally for the treatment of gastrointestinal disorders. The aim of the present study was to investigate the effect of BBR on Th17 cell proliferation and cytokine secretion, and the expression and activation of the signal transducer and activator of transcription 3 (STAT3) transcription factor in OBD in vitro. Blood samples were obtained from healthy controls and patients with active ocular Behcet's disease. Peripheral blood mononuclear cells (PBMCs) or CD4+ T cells were cultured for three days with or without BBR and in the presence of anti­CD3 and anti­CD28 antibodies. IL­17 expression in cell sample supernatants was determined by enzyme­linked immunosorbent assay, and cell viability was measured using the Cell Counting kit­8 assay. The number of CD4+IL­17+ cells and the expression level of phosphorylated (p)­STAT3 in CD4+ T cells was determined using flow cytometry analysis. The expression of IL­17 was increased in patients with active OBD following the activation of PBMCs and CD4+ T cells with anti­CD3 and anti­CD28 antibodies when compared with healthy controls. However, no significant difference in cell viability following exposure to BBR was observed in PBMCs derived from healthy controls or patients with OBD. Following incubation with BBR, the expression of IL­17 was reduced and the number of CD4+IL­17+ cells was decreased in patients with active OBD and healthy controls. Furthermore, the expression of p-STAT3 was significantly decreased in the presence of BBR in healthy controls. In conclusion, the results of the present study demonstrate that BBR may suppress the Th17 response in patients with OBD by reducing STAT3 phosphorylation. BBR may be a potential therapeutic agent for the treatment of OBD.

Biotherapies in Behçet's disease.

Behçet's disease (BD) is a systemic large-vessel vasculitis characterized by a wide clinical spectrum including recurrent oral and genital ulcerations, uveitis, vascular, neurological, articular, renal and gastrointestinal manifestations. Therapeutic management of BD depends on the clinical presentation and organ involved. Although colchicine, nonsteroidal antiinflammatory agents and topical treatments with corticosteroids are often sufficient for mucocutaneous and joint involvements, more aggressive approach with immunosuppressive agents is warranted for severe manifestations such as posterior uveitis, retinal vasculitis, vascular, and neurological and gastrointestinal involvements. However, some patients still have refractory disease, relapse, sight threatening eye disease, or irreversible organ damage. Recent improvements in the understanding of the pathogenic mechanisms have led to the identification of potential targets and future biological therapies for BD. In contrast to current non-specific immunosuppressive agents, the emergence of biotherapies provides the possibility of interfering with specific pathogenic pathways. Novel targeted biotherapies might be used in the future for BD.

New insights in the clinical understanding of Behçet's disease.

Behçet's disease is a chronic relapsing multisystemic inflammatory disorder characterized by four major symptoms (oral aphthous ulcers, genital ulcers, skin lesions, and ocular lesions) and occasionally by five minor symptoms (arthritis, gastrointestinal ulcers, epididymitis, vascular lesions, and central nervous system symptoms). Although the etiology of Behçet's disease is still unknown, there have been recent advances in immunopathogenic studies, genome-wide association studies, animal models, diagnostic markers, and new biological agents. These advances have improved the clinical understanding of Behçet's disease and have enabled us to develop new treatment strategies for this intractable disease, which remains one of the leading causes of blindness.

Hypothalamic proline-rich polypeptide is a regulator of oxidative burst in human neutrophils and monocytes.

OBJECTIVE: The effects of proline-rich polypeptide (PRP) isolated from neurosecretory granules of bovine neurohypophysis produced by nuclei supraopticus and paraventricularis on phagocytosis, bacterial intracellular killing and oxidative burst induction in normal human cells and inflammatory cells from patients with Behçet's disease (BD), i.e. peripheral blood neutrophils and monocytes, were investigated. METHODS: Intracellular killing of Staphylococcus aureus by neutrophils and monocytes of normal controls and BD patients, phagocytic activity as well as spontaneous and N-formyl-Met-Leu-Phe (fMLP)- or phorbol 12-myristate 13-acetate (PMA)-induced activation of their respiratory burst were determined by quantitative flow cytometry using highly specific fluorescence probes. RESULTS: PRP does not affect human peripheral blood neutrophil and monocyte phagocytosis but dramatically enhances spontaneous or fMLP- and PMA-induced oxidative burst as well as the intracellular killing of S. aureus. PRP induced the upregulation of the spontaneous or fMLP- and PMA-induced oxidative burst in normal PMNs and monocytes; the number of inflammatory BD cells did neither increase further nor undergo spontaneous or PMA-stimulated oxidative burst. In BD patients, increased spontaneous production of reactive oxygen intermediates (ROIs) by neutrophils and monocytes is characterized by impaired intracellular protein-kinase-C (PKC)-dependent oxidative burst regulation as well as over-regulation of chemotaxis/inflammation-mediated respiratory burst induction. PRP restores rather the impaired intracellular PKC-dependent regulation of ROI production in inflammatory diseased cells than the chemotaxis/induction of the inflammation-mediated respiratory burst. CONCLUSION: We demonstrated the regulatory role for PRP on oxidative burst in neutrophils and monocytes from normal controls and BD patients. Our results suggest that PRP differentially affects both chemotaxis- and PKC-dependent oxidative burst in normal and inflammatory cells from patients.

Novel effects of On-Chung-Eum, the traditional plant medicine, on cytokine production in human mononuclear cells from Behçet's.

Plant medications have been used as treatment in various kinds of systemic inflammatory disorder such as Behçet's disease (BD). We investigated the roles of On-Chung-Eum (OCE), a traditional plant medicine, in cytokine regulation of BD. The effects of OCE on cytokine production from phytohaemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMC) of Behçet's patients and control subjects were measured by ELISA. PBMC from patients with active BD produced higher levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) compared to control. OCE significantly inhibited the production of TNF-alpha, IL-1beta and interferon-gamma (INF-gamma), compared to absence of OCE. The inhibitory effects of OCE showed in a dose-dependent manner, and OCE had better effects than immunosuppressive drug, cyclosporin A. OCE is able to effectively inhibit proinflammatory cytokines and immunoregulatory Th1 cytokine. OCE treatment for BD patients may help the improvement of symptoms through cytokine modulation.

Clinical study on therapeutic effect of acupuncture on Behcet's disease.

Forty-six cases of Behcet's disease were randomly divided into two groups. The 26 cases in the treatment group were treated by acupuncture and the 20 cases in the control group with the drugs. The level of L-chain (kappa) of IgM and the level of the trace element Zn were determined before and after treatment in the treatment group. The results showed that the recurrence rate in the treatment group was significantly lower than that in the control group (P < 0.01), and the differences in the level of L-chain (kappa) of IgM and level of Zn in the treatment group before and after treatment were very significant (P < 0.01). These two indexes tended to become normal after treatment.

Effects of acupuncture on humoral immunologic function and trace elements in 20 cases of Behcet's disease.

Acupuncture therapy could normalize both increased light chain K value of IgM and lowered trace element Zn content in patients with Behcet's disease with statistically significant differences, suggesting that acupuncture therapy can elevate humoral immunologic function and improve metabolism of the trace element in these patients.

A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3.

A cDNA encoding a novel member of the mitogen-activated protein kinase kinase (MAPKK) family, MAPKK6, was isolated and found to encode a protein of 334 amino acids, with a calculated molecular mass of 37 kDa that is 79% identical to MKK3. MAPKK6 was shown to phosphorylate and specifically activate the p38/MPK2 subgroup of the mitogen-activated protein kinase superfamily and could be demonstrated to be phosphorylated and activated in vitro by TAK1, a recently identified MAPKK kinase. MKK3 was also shown to be a good substrate for TAK1 in vitro. Furthermore, when co-expressed with TAK1 in cells in culture, both MAPKK6 and MKK3 were strongly activated. In addition, co-expression of TAK1 and p38/MPK2 in cells resulted in activation of p38/MPK2. These results indicate the existence of a novel kinase cascade consisting of TAK1, MAPKK6/MKK3, and p38/MPK2.

Selenium and Behçet's disease.

Behçet's disease is an inflammatory disorder of unknown etiology, characterized by recurrent oral and genital aphthous ulcers, ocular inflammation, and skin lesions of erythema nodosum and acneiform eruptions. Selenium (Se) affects all components of the immune system, i.e., the development and expression of nonspecific, humoral, and cell-mediated responses. In general, a deficiency in Se appears to result in immunosuppression, whereas supplementation with low doses of Se appears to result in augmentation and/or restoration of immunologic functions. In this study, the distribution of Se and IgG, IgM in serum were compared in samples from healthy adult control and Behçet's disease patients. The serum Se levels were measured by AA-30-40 Varian Spectra, and immunoglobulins were measured by immunodiffusion technique. The mean (SD) serum Se level of 54.24 +/- 8.06 ng/mL among Behçet's disease subjects was significantly different (P less than 0.01) from that in the control subjects (90.01 +/- 9.94 ng/mL). We also measured IgG and IgM as 10.01 +/- 2.74 mg/mL and 1.26 +/- 0.29 mg/mL, respectively for patients, and 15.08 +/- 4.73 mg/mL and 1.58 +/- 0.43 mg/mL for controls. The mean values of IgG and IgM for patients were significantly (P less than 0.05) different from the values of controls. It seems, therefore, that a deficiency in selenium impedes the humoral immune response.