Activation of alternative NF-kappa B pathway by human herpes virus 8-encoded Fas-associated death domain-like IL-1 beta-converting enzyme inhibitory protein (vFLIP)

The Kaposi's sarcoma-associated herpesvirus (KSHV, also called human herpesvirus 8) has been linked to KS and primary effusion lymphoma (PEL) in immunocompromised individuals. We report that PEL cell lines have constitutive active alternative NF-kappa B pathway and demonstrate high-level expression of NF-kappa B2/p100 precursor and its processed subunit p52. To elucidate the mechanism of activation of the alternative NF-kappa B pathway in PEL cells, we have investigated the role of KSHV-encoded viral Fas-associated death domain-like IL- beta 1-converting enzyme inhibitory protein (vFLIP) K13. We demonstrate that stable expression of K13, but not other FLIPs, in a variety of cell lines constitutively up-regulates p100/NF-kappa B2 expression and leads to its processing into the p52 subunit. K13-induced up-regulation and processing of p100 critically depends on the I kappa B kinase (IKK)alpha/IKK1 subunit of the IKK complex, whereas IKK beta/IKK2, receptor-interacting protein, and NF-kappa B-inducing kinase are dispensable for this process. Silencing of endogenous K13 expression by siRNA inhibits p100 processing and cellular proliferation. Our results demonstrate for the first time, to our knowledge, that KSHV vFLIP K13 is required for the growth and proliferation of PEL cells and alternative NF-kappa B pathway plays a key role in this process. Therapeutic agents targeting the alternative NF-kappa B pathway may have a role in the treatment of KSHV-associated lymphomas.     

Recombinant Human Interleukin-6 Induces Hepatocyte Growth Factor Production in Cancer Patients

Background: Experiments in animals demonstrate an important role for interleukin-6 (IL-6) in liver regeneration. It is suggested that IL-6 initiates hepatocyte growth factor (HGF) synthesis. Methods: The aim of the study was to examine the effect of exogenously administered recombinant human IL-6 (rhIL6), in doses of 0.5, 1.0, 2.5, 5, 10 and 20 µg/kg/day, on HGF serum levels in humans. Serum HGF levels were measured on days 1, 2, 3, 8 and 15 and were correlated with serum amyloid A (SAA) and C-reactive protein (CRP). Results: Median HGF levels increased to 124% at day 3 (P < 0.05) and 157% (P < 0.05) at day 8 as compared to 100% levels at day 1. An IL-6 dose-dependent increase in HGF was found at day 8 (R = 0.53, P < 0.02). The percentual change in serum HGF level at day 8 correlated with IL-6 serum levels at day 1 R = 0.59, P < 0.01). HGF levels did not correlate with CRP and SAA. Conclusion: In humans, rhIL-6 administration resulted in an increase in serum HGF levels.     

Interleukin-8 (IL-8) in synovial fluid of rheumatoid and nonrheumatoid joint effusions

Summary IL-8 was measured in knee joint synovial fluid of 60 patients with rheumatoid arthritis, 8 with gout, 6 with osteoarthritis and 4 with meniscus lesions. IL-8 could be demonstrated in most SF samples. The highest levels were observed in rheumatoid joint effusions, yet mean levels were not significantly different between the different subgroups (mean±SE; RA 1537±3049 pg/ml, gout 570±952 pg/ml, OA/ML 178±188 pg/ml). In RA patients, IL-8 levels could not be related to various serological, clinical or radiological parameters. However, a correlation was observed between SF levels of IL-8 with those of lactate, LDH, 2-microglobulin and glucose. These observations suggest that next to the laboratory parameters IL-8 will be a parameter of the activity of the local inflammatory process. The results also demonstrate that IL-8 is not a disease-specific marker of joint inflammation.     

同型半胱氨酸诱导培养的人脐静脉内皮细胞分泌白细胞介素8

为探讨同型半胱氨酸对内皮细胞分泌白细胞介素 8的影响 ,及叶酸和牛磺酸对同型半胱氨酸作用的影响 ,将人脐静脉内皮细胞培养于不同浓度同型半胱氨酸中 ,采用酶联免疫吸附试验测定培养基中白细胞介素 8水平。结果发现 ,培养于同型半胱氨酸 (0 .1mmol L)中 4h、6h、8h和 1 2h ,白细胞介素 8分泌水平分别是对照组的1 .85倍、1 .88倍、2 .2 2倍和 1 .5 6倍 (P <0 .0 1 ) ;在不同浓度 (0 .0 5mmol L、0 .1mmol L、0 .5mmol L和 1mmol L)同型半胱氨酸中培养 8h ,各组内皮细胞白细胞介素 8的分泌水平分别是对照组的 1 .4 3倍、2 .1 6倍、2 .5 7倍和 2 .88倍(P <0 .0 5或P <0 .0 1 ) ,并呈剂量依赖性 ;同型半胱氨酸与叶酸 (0 .0 5mmol L)或牛磺酸 (5mmol L)共同培养细胞 ,各组内皮细胞白细胞介素 8的分泌水平无显著差异 (P >0 .0 5 )。以上结果提示 ,病理浓度的同型半胱氨酸能刺激内皮细胞分泌白细胞介素 8增加 ,这可能是同型半胱氨酸致动脉粥样硬化的机制之一 ;叶酸和牛磺酸可能阻断同型半胱氨酸的这一作用     

Helicobacter pylori-Stimulated Interleukin-8 (IL-8) Promotes Cell Proliferation Through Transactivation of Epidermal Growth Factor Receptor (EGFR) by Disintegrin and Metalloproteinase (ADAM) Activation

Helicobacter pylori infection increases the risk of hyperplastic polyps and gastric cancer, but the mechanisms remain to be elucidated. H. pylori was recently shown to transactivate epidermal growth factor receptor (EGFR) through metalloprotease stimulation. The present study was designed to investigate the effect of interleukin-8 (IL-8) induced by H. pylori infection on EGFR transactivation and epithelial cell growth. H. pylori Sydney strain 1 (SS1) having wild-type cag⁺A was used. Phospho-EGFR assay was performed by immunoprecipitation using anti-human EGFR and anti-phosphotyrosine antibodies. DNA synthesis was evaluated by [³H]thymidine uptake using the human gastric cancer cell line, KATO III. H. pylori induced EGFR phosphorylation, and a disintegrin and metalloproteinase (ADAM) inhibitor, KB-R7785, completely suppressed EGFR phosphorylation. IL-8 also induced EGFR phosphorylation, while anti-IL-8 and anti-IL-8 receptor (CXCR1) neutralizing antibodies suppressed EGFR phosphorylation. [³H]Thymidine uptake analysis demonstrated that H. pylori increased DNA synthesis in gastric epithelial cells, and tyrosine kinase inhibitor, MEK inhibitor, and ADAM inhibitor suppressed the DNA synthesis induced by H. pylori. H. pylori-stimulated IL-8 accelerates processing of EGFR ligands through ADAM activation, and cleaved EGFR ligands bind and stimulate EGFR in paracrine and autocrine manners to induce cell proliferation. This may be one of the mechanisms of hyperplastic polyp and gastric cancer development in H. pylori-infected gastric mucosa.     

Interleukin-8 (IL-8): the major neutrophil chemotactic factor in the lung

A number of novel chemotactic cytokines are becoming increasingly recognized as important participants in the elicitation of specific inflammatory cells from the peripheral blood to sites of inflammation. Recent observations have now demonstrated that certain chemotactic cytokines possess specificity for the selected movement of individual immune/inflammatory cell populations. One of the more studied chemotactic cytokines is a neutrophil chemotactic factor identified as interleukin-8 (IL-8). This polypeptide mediator is produced in abundance by mononuclear phagocytic cells, as well as a number of non-inflammatory cells. This latter list includes both fibroblasts and epithelial cells. Moreover, the synthesis of IL-8 by fibroblasts and epithelial cells involves stimulus specificity, as the production of this mediator by non-inflammatory cells is dependent upon an initial host response. In the context of the lung, the alveolar macrophage appears to play a central role by generating factors, such as interleukin-1 and tumor-necrosis factor, which are potent stimuli for the induction of IL-8 by the lung fibroblasts and type II epithelial cells. The cascade-like interaction may lead to the rapid production of significant quantities of IL-8 by the lung and may selectively recruit neutrophils to the pulmonary interstitium and/or airspace. This sequence of events, which leads to cytokine networking in the lung, may be an important phenomenon for the generation of a major chemotaxin important to a variety of lung diseases.