Interfreron-α Alone versus Interferon-α plus Ribavirin in Patients with Chronic Hepatitis C Not Responding to Previous Interferon-α Treatment

OBJECTIVE: To study the effects of monotherapy with leucocyte interferon-alpha (IFNalpha) versus IFNalpha + ribavirin in patients with chronic hepatitis C who were nonresponders to previous courses of recombinant or lymphoblastoid IFNalpha. DESIGN AND SETTING: This was a nonblind randomised study of outpatients at 3 centres in Palermo, Sicily, Italy. PATIENTS AND PARTICIPANTS: We recruited 72 patients (48 males, 24 females), mean age 48.8 +/- 6.6 years (range 31 to 63 years), with biopsy-proven chronic hepatitis C, predominantly genotype 1b. INTERVENTIONS: 24 patients (group A) received IFNalpha 6MU 3 times weekly for 6 months, and 48 patients (group B) received IFNalpha 6MU 3 times weekly + ribavirin 1200 mg/day for 6 months. ALT levels and adverse effects were monitored monthly, and hepatitis C virus (HCV) RNA levels were measured at study entry, at the end of treatment and after a 6-month follow-up. RESULTS: At baseline all patients were HCV-RNA positive and had ALT levels greater than twice normal. Mean post-treatment serum HCV-RNA levels were below baseline in group A, but the virus was eradicated in only 1 patient; 6 patients had normalised serum ALT levels. In group B at end of treatment, 12 patients were negative for HCV-RNA and serum ALT levels were normal in 18. At follow-up, all group A patients had elevated ALT levels and positive HCV-RNA. In group B, 3 patients were still negative for HCV-RNA and 4 had normal ALT. In 4 patients in group B, therapy was suspended because of anaemia, depression and decrease in neutrophil count; a flu-like syndrome was recorded with no frequency difference between groups. CONCLUSIONS: These results suggest that patients with chronic hepatitis C unresponsive to IFNalpha monotherapy could benefit from combination therapy with IFNalpha + ribavirin.     

TNF-α and Chronic Fatigue Syndrome

Based upon the clinical presentation of chronic fatigue syndrome (CFS), we hypothesized that proinflammatory cytokines may play a role in the pathogenesis of the disease. We therefore undertook a retrospective cross-sectional study to examine the role of TNF- in patients with CFS. Our results suggest a significant increase serum TNF- in patients with CFS (P < 0.0001) compared to non-CFS controls. This study supports the further examination of the role of proinflammatory mediators in CFS. Furthermore, the clinical testing of TNF- blockers and other antiinflammatory agents for the treatment of this disease is warranted.     

血清TNF-α RIA及其临床意义

肿癌坏死因子α(Tumour necrosis factoralpha,TNF-α)是由单核巨噬细胞所产生的一种多肽，不仅具有使肿癌坏死退化的作用且参与抗感染、凝血、发热、休克、多器官功能衰竭、恶病质等多种病理生理过程，对白细胞、内皮细胞等各种细胞的功能以及某些细胞的生长与分化均有激素样作用。本文报告了用放免法测定的正常人及病人血清TNF4α值，并对其意义进行了探讨。     

Impact of TNF-α and LTα gene polymorphisms on genetic susceptibility in Indian SLE patients

The promoter polymorphisms of tumour necrosis factor-α (TNF-α) and intronic Lymphotoxin-α (LTα) have been implicated as genetic risk factors for systemic lupus erythematosus (SLE) in various ethnic groups. The aim of this study was to investigate an impact of TNF-α (?308G/A; 238G/A) and LTα (+252A/G) gene polymorphisms in disease susceptibility among Indian 200 SLE patients along with 201 healthy controls. The gene polymorphisms were studied by using direct DNA sequencing and Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) methods. Serum levels were measured by multiplex assay. Allelic frequencies of TNF-α ?308A (OR = 2.3, p = 0.0001, Pc = 0.0003) and LTα +252G (OR = 2.1, p < 0.0001, Pc < 0.001) were significantly higher in SLE patients. Frequency of haplotype-AGG was found to be higher in patients than controls (OR = 12.2, p = 0.0050). Serum levels of TNF-α and LTα also were found to be significantly higher in patients showing variant alleles. TNF-α ?308G/A + A/A genotypes (p < 0.01) and LTα +252 A/G + G/G genotypes (p < 0.02) were significantly associated with renal disorders and haematological manifestations. SLE patients with ?308G/A + A/A genotypes showed higher prevalence of anti-dsDNA antibodies (OR = 3.9, p = 0.0014, Pc = 0.0098) and anti-Sm antibodies (OR = 4.1, p = 0.0002, Pc = 0.0014). The present study suggests TNF-α ?308A and LTα +252G as risk alleles for disease susceptibility associated with higher serum levels of TNF-α and LTα and concomitant discrete clinical features among Indian SLE patients.     

Bestimmung desα 2-Haptoglobinspiegels bei Nierenerkrankungen

Ohne ZusammenfassungMit freundlicher Unterstützung der Deutschen Forschungsgemeinschaft.     

Potential of Interferon-α in Solid Tumours

Interferon-alpha (IFNalpha) is a pleiotropic cytokine with direct and indirect antitumour effects. These include prolongation of the cell cycle time of malignant cells, inhibition of biosynthetic enzymes and apoptosis, interaction with other cytokines, and immunomodulatory and antiangiogenic effects. The first clinical trials in solid tumours used crude preparations of natural IFNalpha and demonstrated that tumour regressions in solid tumours and haematological malignancies were possible. Since the advent of genetic engineering technology, recombinant (r) IFNalpha has been widely evaluated in solid tumours. This review discusses the use and potential of rIFNalpha in solid tumours; the first part focuses on malignant melanoma and metastatic renal cell carcinoma (RCC). In the adjuvant treatment of malignant melanoma, rIFNalpha has been tested in randomised trials in more than 6000 patients. High-dosage IFNalpha (> or =10MU) prolongs disease-free survival (DFS) but not overall survival (OS). Low-dosage IFNalpha (< or =3MU) has not been shown to prolong DFS or OS, and current data do not support its use outside clinical trials. The latest United Kingdom Co-ordinating Committee on Cancer Research meta-analysis of ten randomised trials that used adjuvant rIFNalpha has shown that there is a benefit in DFS but not OS. No conclusions can be reached for intermediate-dosage IFNalpha (5 to 10MU) until the mature results of the European Organization for Research and Treatment of Cancer (EORTC) study 18952 are available. In RCC, current evidence does not support the use of adjuvant IFNalpha. In metastatic malignant melanoma and RCC, reported response rates to rIFNalpha are approximately 15%. In a minority of responding patients, however, these responses can be long-standing. In metastatic malignant melanoma, IFNalpha combined with other cytotoxic agents with or without interleukin-2 has achieved high response rates but has not improved survival. In metastatic RCC, intermediate dosages of rIFNalpha should be used and therapy should probably be prolonged (>12 months); response depends on prognostic factors such as good performance status, whereas survival is affected by factors such as low tumour burden. Nephrectomy should therefore be considered in patients with good performance status prior to IFNalpha immunotherapy in advanced RCC, even in patients with metastatic disease. The toxicity of high-dosage IFNalpha and the lack of definite benefit on OS with high- or low-dosage IFNalpha do not support its use outside clinical trials. Data from the ongoing US Intergroup studies, the ongoing EORTC 18991 study (long-term therapy with pegylated IFNalpha) and mature data from EORTC 18952 (intermediate-dosage IFNalpha) will help establish the role of IFNalpha as adjuvant therapy in malignant melanoma.     

雌激素受体α 共激活子与乳腺癌

在乳腺癌发生发展过程中,雌激素受体（estrogen receptor α ,ERα）信号途径的活性增强,一个重要的原因是ERα共调节因子的变化。ERα共调节因子可分为共激活子和共抑制子。本文对ERα共激活子的种类、与ERα的结合方式、作用机制及其与乳腺癌的关系进行了综述。     

Potential Mechanisms of Interferon-α Induced Autoimmunity

The type I interferons (IFN) are cytokines encoded by a multigene family comprising 13 closely related IFN-A genes, and a single IFN-B gene. These factors are rapidly induced upon viral infection, and have pleiotropic effects. Historically, the induction of a cell-autonomous state of antiviral resistance, the inhibition of cell growth, and the regulation of apoptosis were appreciated first. More recently, it became generally accepted that they can regulate immune effector functions. This latter feature led them to be reconsidered as signals linking innate and adaptive immunity, and potentially orchestrating autoimmunity associated with viral infection and IFN-α therapy. Common to almost all autoimmune diseases is their polygenic inheritance, incomplete penetrance, and evidence for the role of environmental factors, particularly viral infection. In addition, they are characterized by increased numbers of circulating autoreactive T- and B-cells. Endogenously produced or therapeutically applied IFN-α can tilt the usually tightly controlled balance towards activation of these autoreactive cells via a vast array of mechanisms. The genetic susceptibility factors determine which type of autoimmunity will develop. IFN-α induces numerous target genes in antigen presenting cells (APC), such that APC are stimulated and enhance humoral autoimmunity, promote isotype switching, and potently activate autoreactive T cells. Moreover, IFN-α can synergistically amplify T cell autoreactivity by directly promoting T cell activation and keeping activated T cells alive. In essence, type I IFNs may constitute one example of genes that have been conserved because they confer dominant disease resistance, but at the same time they can trigger autoimmunity in genetically susceptible individuals.     

Tumor necrosis factor-α signaling in macrophages

Tumor necrosis factor-α (TNFα) was cloned over 2 decades ago and its identification in part led to the discovery of a super family of tumor necrosis factors (TNFs) and their receptors. TNFα signals through two transmembrane receptors, TNFR1 and TNFR2, and regulates a number of critical cell functions including cell proliferation, survival, differentiation, and apoptosis. Macrophages are the major producers of TNFα and interestingly are also highly responsive to TNFα. Aberrant TNFα production and TNF receptor signaling have been associated with the pathogenesis of several diseases, including rheumatoid arthritis, Crohn's disease, atherosclerosis, psoriasis, sepsis, diabetes, and obesity. TNFα has been shown to play a pivotal role in orchestrating the cytokine cascade in many inflammatory diseases and because of this role as a "master-regulator" of inflammatory cytokine production, it has been proposed as a therapeutic target for a number of diseases. Indeed anti-TNFα drugs are now licensed for treating certain inflammatory diseases including rheumatoid arthritis and inflammatory bowel disease. In this review we discuss the discovery of TNFα and its actions especially in regulating macrophage biology. Given its importance in several human diseases, we also briefly discuss the role of anti-TNFα therapeutics in the treatment of inflammatory diseases.     

Alternation of interleukin-1α production and interleukin-1α binding sites in mouse brain during rabies infection

Summary We have evaluated the effect of rabies virus infection on interleukin-1(IL-1) production and its receptors in mouse brain. Study of virus dissemination in the central nervous system (CNS) showed a massive infection of main brain structures from day 4 post infection (p.i.) up to the agony stage on day 6 p.i. At the same time, IL-1 concentrations increased in cortical and hippocampal homogenates, whereas no change was detected in serum. In non-infected mice, IL-1 binding sites were observed in the dentate gyrus, the cortex, the choroid plexus, the meninges and the anterior pituitary. During rabies virus infection, a striking decrease in IL-1 binding sites was observed on day 4 p.i. with a complete disappearance on day 6 p.i., except in the pituitary gland where they remained at control level. In conclusion, concomitantly with the early rabid pathological signs, brain IL-1 production and IL-1 binding sites are specifically and significantly altered by brain viral proliferation. These results indicate that IL-1 could be involved in the brain response to viral infection as a mediator and could participate in the genesis of the rabies pathogeny.     

TNF-α and neuropathic pain - a review

Tumor necrosis factor alpha (TNF-α) was discovered more than a century ago, and its known roles have extended from within the immune system to include a neuro-inflammatory domain in the nervous system. Neuropathic pain is a recognized type of pathological pain where nociceptive responses persist beyond the resolution of damage to the nerve or its surrounding tissue. Very often, neuropathic pain is disproportionately enhanced in intensity (hyperalgesia) or altered in modality (hyperpathia or allodynia) in relation to the stimuli. At time of this writing, there is as yet no common consensus about the etiology of neuropathic pain - possible mechanisms can be categorized into peripheral sensitization and central sensitization of the nervous system in response to the nociceptive stimuli. Animal models of neuropathic pain based on various types of nerve injuries (peripheral versus spinal nerve, ligation versus chronic constrictive injury) have persistently implicated a pivotal role for TNF-α at both peripheral and central levels of sensitization. Despite a lack of success in clinical trials of anti-TNF-α therapy in alleviating the sciatic type of neuropathic pain, the intricate link of TNF-α with other neuro-inflammatory signaling systems (e.g., chemokines and p38 MAPK) has indeed inspired a systems approach perspective for future drug development in treating neuropathic pain.     

Stimulation of TNFα expression by hyperosmotic stress

Hyperosmotic stress is known to induce apoptotic cell death, an effect previously attributed to seemingly ligand-independent clustering of tumour necrosis factor alpha (TNF alpha) receptors. An alternative explanation for the clustering of TNF alpha receptors may be stimulation of TNF alpha production, with subsequent autocrine or paracrine stimulation of the receptors. The present study was performed to test for an effect of exposure to hyperosmotic extracellular fluid on cellular TNF alpha production. In both the macrophage cell line U937 and the B lymphocyte cell line LCL721, an increase of extracellular osmolarity to 500 mosmol/l indeed increased TNF alpha expression, an effect reversed by the p38 kinase inhibitor SB203580. In both cell types hyperosmotic stress triggered apoptosis, which in U937 cells was significantly inhibited by neutralizing antibodies against TNF alpha and by SB203580 and was similarly elicited by exogenous addition of TNF alpha. In contrast, osmotically induced apoptosis of LCL721 cells was only slightly blunted by anti-TNF alpha antibodies and rather increased by SB203580. In conclusion, through activation of p38 kinase hyperosmotic stress stimulates the expression of TNF alpha which at least in U937 macrophages may participate in the triggering of subsequent apoptotic cell death. However, the observations in LCL721 cells point to other, TNF alpha-independent, mechanisms mediating apoptotic cell death following an excessive increase of extracellular osmolarity.     

Complications of TNF-α antagonists and iron homeostasis

TNF-α is a central regulator of inflammation and its blockade downregulates other pro-inflammatory cytokines, chemokines, and growth factors. Subsequently, TNF-α antagonists are currently used in treatment regimens directed toward several inflammatory diseases. Despite a beneficial effect, the use of TNF-α antagonists is associated with an increased risk for infections and neoplasms; the basis for these complications is unclear. This cytokine also participates in iron homeostasis and the sequestration of this metal, mediated by TNF-α, is considered protective. We hypothesize that treatment with TNF-α antagonists predisposes the patient to infections and neoplasms by reversing the sequestration of host iron mediated by the cytokine and increasing available concentrations of this metal. It is recommended that patients who are to receive TNF-α antagonists be tested for iron overload and the use of these agents in those individuals with excess iron should be reconsidered. Furthermore, it is predicted that alternative attempts to treat inflammatory diseases by blocking other pivotal cytokines that also participate in iron homeostasis (e.g. IFN-γ, IL-1, and IL-6) will similarly be associated with infections and neoplastic complications.     

NLS-RARα Inhibits the Effects of All-trans Retinoic Acid on NB4 Cells by Interacting with P38α MAPK

Nuclear localization signal retinoic acid receptor alpha(NLS-RARα), which forms from the cleavage of promyelocytic leukemia-retinoic acid receptor alpha(PML-RARα) protein by neutrophil elastase(NE), possesses an important role in the occurrence and development of acute promyelocytic leukemia(APL). However, the potential mechanism underlying the effects of NLS-RARα on APL is still not entirely clear. Here, we investigated the effects of NLS-RARα on APL NB4 cells and its mechanism. We found that all-trans retinoic acid(ATRA) could promote differentiation while inhibit proliferation of APL NB4 cells via upregulating the expression of phosphorylated p38α mitogen-activated protein kinase(p-p38α MAPK). We also found that NLS-RARα could inhibit differentiation while accelerate proliferation of NB4 cells via downregulating the expression of p-p38α protein in the presence of ATRA. Furthermore, immunofluorescence and co-immunoprecipitation assays confirmed NLS-RARα interacted with p38α protein directly. Finally, application of PD169316, an inhibitor of p38α protein, suggested that recruitment p38α-combinded NLS-RARα by ATRA eventually caused activation of p38α protein. In summary, our study demonstrated that ATRA cound promote differentiation while inhibit proliferation of APL NB4 cells via activating p38α protein after recruiting p38α-combinded NLS-RARα, while NLS-RARα could inhibit the effects of ATRA in the process.