Fish TNF and TNF receptors.

Tumor necrosis factors (TNFs) are a group of cytokines that play critical roles in regulating a diverse range of physiological processes in vertebrates. TNFs function by activating a large number of structurally related receptors, leading to TNF mediated biological processes which are evolutionarily conserved. Fish have a much diversified TNF family, partly due to the whole genome duplication events which have occurred in this lineage, providing an excellent model to investigate the neo- and sub-functionalised properties of TNF superfamily. Fish possess most of the TNFs and receptors found in mammals and also some homologues exclusively present in fish. It seems that TNFSF4 (OX40), TNFSF7 (CD27) and TNFSF8 (CD30) and their cognate receptors are absent in teleosts. It has been shown that fish viruses are able to produce TNFR homologues to establish infection by manipulating the host immune system. Understanding the roles of TNFSFs in fish immune defence and the pathogenesis of fish diseases will provide insights into the functions of TNFSFs from an evolutionary perspective and better strategies for improving fish health and welfare in aquaculture. This review summarises recent advances in the study offish TNF biology and focuses on the molecular properties and immunological functions of the TNF and TNFR superfamily.

Safety and tolerability of a single dose T0001 in Chinese healthy adult volunteers: a first-in-human ascending dose study

T0001 is the first mutant of etanercept with a higher affinity to tumor necrosis factor α (TNF-α) than etanercept. In order to investigate the safety and tolerability of T0001, a study was carried out in healthy Chinese subjects. A first-in-human, dose escalation study was conducted in healthy Chinese subjects. Fifty-six subjects were divided into six dose cohorts (10 mg, 20 mg, 35 mg, 50 mg, 65 mg and 75 mg) to receive a single subcutaneous injection of T0001. Safety and tolerability assessment were based on the records of vital signs, physical examinations, clinical laboratory tests, 12-lead electrocardiograms and adverse events (AEs). All subjects were in good compliance and none withdraw due to AEs. No serious AEs occurred. A total of twenty-three AEs in sixteen subjects were recorded, and eighteen of these AEs were believed to be related to T0001. The most frequently reported AEs were injection site reactions and white blood cell count increase. All these AEs were of mild to moderate intensity and most of them recovered spontaneously within 14 days. In this study, no dose-limiting toxicity was observed, and the maximum tolerated dose was identified as 75 mg. T0001 was considered safe and generally well tolerated at doses up to 75 mg in healthy Chinese volunteers

The Major Histocompatibility Complex of Old World Camels-A Synopsis.

This study brings new information on major histocompatibility complex (MHC) class III sub-region genes in Old World camels and integrates current knowledge of the MHC region into a comprehensive overview for Old World camels. Out of the MHC class III genes characterized, TNFA and the LY6 gene family showed high levels of conservation, characteristic for MHC class III loci in general. For comparison, an MHC class II gene TAP1, not coding for antigen presenting molecules but functionally related to MHC antigen presenting functions was studied. TAP1 had many SNPs, even higher than the MHC class I and II genes encoding antigen presenting molecules. Based on this knowledge and using new camel genomic resources, we constructed an improved genomic map of the entire MHC region of Old World camels. The MHC class III sub-region shows a standard organization similar to that of pig or cattle. The overall genomic structure of the camel MHC is more similar to pig MHC than to cattle MHC. This conclusion is supported by differences in the organization of the MHC class II sub-region, absence of functional DY genes, different organization of MIC genes in the MHC class I sub-region, and generally closer evolutionary relationships of camel and porcine MHC gene sequences analyzed so far.

Acute cold stress improved the transcription of pro-inflammatory cytokines of Chinese soft-shelled turtle against Aeromonas hydrophila.

Chinese soft-shelled turtle, Pelodiscus sinensis, is widely cultured in East and Southeast Asian countries. It frequently encounters the stress of abrupt temperature changes, which leads to mass death in most cases. However, the mechanism underlying the stress-elicited death remains unknown. We have suspected that the stress impaired the immune function of Chinese soft-shelled turtle, which could result in the mass death, as we noticed that there was a clinical syndrome of infection in dead turtles. To test our hypothesis, we first performed bioinformatic annotation of several pro-inflammatory molecules (IL-1ß, TNFα, IL-6, IL-12ß) of Chinese soft-shelled turtle. Then, we treated the turtles in six groups, injected with Aeromonas hydrophila before acute cold stress (25 °C) and controls, after acute cold stress (15 °C) and controls as well as after the temperature was restored to 25 °C and controls, respectively. Subsequently, real-time PCR for several pro-inflammatory cytokines (IL-1ß, TNFα, IL-6, IL-12ß, IL-8 and IFNγ) was performed to assess the turtle immune function in spleen and intestine, 24 hours after the injection. We found that the mRNA expression levels of the immune molecules were all enhanced after acute cold stress. This change disappeared when the temperature was restored back to 25 °C. Our results suggest that abrupt temperature drop did not suppress the immune function of Chinese soft-shelled turtle in response to germ challenge after abrupt temperature drop. In contrast, it may even increase the expression of various cytokines at least, within a short time after acute cold stress.

Two types of TNF-α exist in teleost fish: phylogeny, expression, and bioactivity analysis of type-II TNF-α3 in rainbow trout Oncorhynchus mykiss.

TNF-α is a cytokine involved in systemic inflammation and regulation of immune cells. It is produced chiefly by activated macrophages as a membrane or secreted form. In rainbow trout, two TNF-α molecules were described previously. In this article, we report a third TNF-α (TNF-α3) that has only low identities to known trout molecules. Phylogenetic tree and synteny analyses of trout and other fish species suggest that two types (named I and II) of TNF-α exist in teleost fish. The fish type-II TNF-α has a short stalk that may impact on its enzymatic release or restrict it to a membrane-bound form. The constitutive expression of trout TNF-α3 was generally lower than the other two genes in tissues and cell lines, with the exception of the macrophage RTS-11 cell line, in which expression was higher. Expression of all three TNF-α isoforms could be modulated by crude LPS, peptidoglycan, polyinosinic:polycytidylic acid, and rIFN-γ in cell lines and primary macrophages, as well as by bacterial and viral infections. TNF-α3 is the most responsive gene at early time points post-LPS stimulation and can be highly induced by the T cell-stimulant PHA, suggesting it is a particularly important TNF-α isoform. rTNF-α3 produced in CHO cells was bioactive in different cell lines and primary macrophages. In the latter, it induced the expression of proinflammatory cytokines (IL-1ß, IL-6, IL-8, IL-17C, and TNF-αs), negative regulators (SOCS1-3, TGF-ß1b), antimicrobial peptides (cathelicidin-1 and hepcidin), and the macrophage growth factor IL-34, verifying its key role in the inflammatory cytokine network and macrophage biology of fish.

Uso intermitente de etanercept en psoriasis / Intermittent use of etanercept in psoriasis

Para el tratamiento de la psoriasis en placas moderada-grave en España, hasta hace muy poco, únicamente estaba aprobado el uso de etanercept de forma intermitente o en ciclos de tratamiento no superiores a 24 semanas. A partir de septiembre de 2009 se aprobó su administración ininterrumpida para aquellos pacientes con psoriasis moderada-grave que, a criterio médico, así lo requieran. Esta decisión está avalada por los resultados de varios estudios que evaluaban la eficacia y seguridad de etanercept a corto y largo plazo, en terapia continua o intermitente. El estudio CRYSTEL evalúa la eficacia y seguridad de etanercept en tratamiento continuo o intermitente durante 54 semanas. Los resultados demostraron que tanto los pacientes que recibieron tratamiento continuo como los que recibieron tratamiento intermitente experimentaron mejorías significativas en su enfermedad y se mostraron muy satisfechos con el resultado, sin observarse hallazgos inesperados de seguridad en ambos grupos (AU)

Systemic treatment for psoriasis has radically changed since the emergence of new biological therapies. One of these biological agents is etanercept. Until recently, the use of etanercept for treatment of moderate-to-severe psoriasis in Spain was only approved in an intermittent way or in cycles of treatment (not exceeding 24 weeks). However, from September 2009, its administration has been also approved in a continuous way for patients who require it. This decision is based on the results of several studies that evaluate the efficacy and safety of etanercept administrated in short and long term and in a continuous or intermittent therapy. One of these studies is Crystel study, what evaluates the efficacy and safety of continuous and paused etanercept regimens in psoriasis patients for 54-week-period. Crystel study results showed that both continuous and paused etanercept therapies improved PGA and PASI scores and patient satisfaction rates, no unexpected adverse effects were observed. Therefore, doctors may use one treatment or another according to patients needs (AU)

Artritis psoriásica y etanercept / Psoriatic arthritis and etanercept

La artritis psoriásica (APs) es una enfermedad inflamatoria crónica cuyos síntomas suelen aparecer después de los cutáneos. Resulta de vital importancia la realización de un diagnóstico y tratamiento precoz de la enfermedad debido al potencial desarrollo de artritis deformante o mutilante. Los tratamientos clásicos de la APs incluyen la utilización de antiinflamatorios no esteroideos, fármacos antirreumáticos modificadores de la enfermedad (FAME), como metotrexato, sulfasalazina o el oro y, últimamente, leflunomida. Las investigaciones sobre la fisiopatología de la psoriasis y de la APs han llevado a la incorporación de los tratamientos biológicos, concretamente los fármacos anti-factor de necrosis tumoral (TNF). Los tres tratamientos más utilizados en APs son etanercept, infliximab y adalimumab. De todos ellos vamos a hacer una revisión sistemática de los principales estudios disponibles de etanercept para el tratamiento de la APs (AU)

Psoriatic arthritis (PA) is a chronic inflammatory condition whose symptoms generally appear after the skin symptoms. Making an early diagnosis and treatment of the disease is of vital importance because of the potential development of mutilating and deforming arthritis. Classical treatments of PA include the use of non-steroid anti-inflammatory drugs, diseasemodifying antirheumatic drugs (DMARD) such as methotrexate, sulfasalazine, or gold, and finally, leflunomide. Research on the pathophysiology of psoriasis and of the PA has led to the incorporation of biological treatments, specifically anti-TNF drugs. The three treatments used most in PA are etanercept, infliximab and adalimumab. Of all these, we are going to make a systematic review of the principal studies available on etanercept for the treatment of PA (AU)

Psoriasis pustulosa, psoriasis palmoplantar, psoriasis eritrodérmica y etanercept / Pustular psoriasis, palmoplantar psoriasis, erythodermal psoriasis and etanercept

Etanercept está aprobado para el tratamiento de la psoriasis en placas moderada-grave; esta es la forma más frecuente de psoriasis (80%). En otras formas de psoriasis el uso de etanercept, al igual que el de otras terapias biológicas, se ha publicado de forma aislada con resultados satisfactorios. Presentamos el caso de una paciente con psoriasis palmoplantar pustulosa refractaria a múltiples tratamientos (corticoides tópicos, fototerapia, metotrexato) que respondió favorablemente al uso de etanercept a dosis de 50 mg dos veces por semana. La paciente ha mantenido una remisión total de las lesiones tras 6 meses de finalizar el tratamiento. Resumen: Revisamos los casos publicados de psoriasis palmoplantar tratados con etanercept y también el uso de este fármaco en otras formas de psoriasis pustulosa y de psoriasis eritrodérmica (AU)

Etanercept has been approved for the treatment of moderate-severe plaque psoriasis. This is the most frequent form of psoriasis (80%). In other forms of psoriasis, the use of etanercept, as that of other biological therapies, has been published in an isolated way with satisfactory results. We present a patient with palmoplantar pustulous psoriasis palmoplantar refractory to multiple treatments (topical corticosteroids, phototherapy, methotrexate) who responded favorably to the use of 50 mg biweekly doses of etanercept. The patient has maintained total remission of the lesions 6 months after having terminated treatment. We review the cases published on palmoplantar psoriasis treated with etanercept and also the use of this drug in other forms of pustular psoriasis and of erythrodermal psoriasis (AU)

Infliximab / Infliximab

Infliximab es un anticuerpo quimérico monoclonal que se une específicamente al factor de necrosistumoral alfa (TNF-α) y bloquea su actividad. Múltiples ensayos clínicos, basándose en evidencias previas relacionadascon el papel del TNF-α en la patogénesis de la psoriasis, han demostrado que infliximab consigue un alto grado de beneficio clínico en el tratamiento de la psoriasis y artritis psoriásica, permitiendo alcanzar una mejoría importante y rápida en estos pacientes. Revisamos diferentes ensayos clínicos que demuestran la eficacia y la seguridad de infliximab en el tratamiento de psoriasis moderada a severa y artritis psoriásica (AU)

Infliximab is a chimeric monoclonal antibody, which specifically binds to tumor necrosis factor (TNF-α) and blocks its activity. Based on previous evidence that TNF-αhas been involved in the pathogenesis of psoriasis, multiple controlled trials have shown that infliximab has provided a high degree of clinical benefit in the treatment of psoriasis and psoriatic arthritis allowing a major and rapid improvement in these patients.We review several clinical trials, which have firmly established both efficacy and safety of Infliximab in the treatment of moderate to severe psoriasis and psoriatic arthritis (AU)

Identification of a novel 120 bp allele at the TNFd microsatellite locus.

Tumor necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine mainly secreted by macrophages and T-cells that play a key role in the pathogenesis of many infectious and inflammatory diseases. The TNF gene cluster is located within the class-III region of the highly polymorphic major histocompatibility complex on human chromosome 6p21. A cluster of six multiallelic microsatellites has been identified in the TNF region, named TNF a-e. TNFb, TNFc, TNFd, and TNFe are (GA)n repeats, whereas TNFa and TNFf are (GT)n and (CA)n repeats, respectively. The TNFd microsatellite locus maps 8-10 kb centromeric to the TNF-alpha gene, downstream to the TNF-beta gene.

Gene expression patterns in dendritic cells infected with measles virus compared with other pathogens.

Gene expression patterns supply insight into complex biological networks that provide the organization in which viruses and host cells interact. Measles virus (MV) is an important human pathogen that induces transient immunosuppression followed by life-long immunity in infected individuals. Dendritic cells (DCs) are potent antigen-presenting cells that initiate the immune response to pathogens and are postulated to play a role in MV-induced immunosuppression. To better understand the interaction of MV with DCs, we examined the gene expression changes that occur over the first 24 h after infection and compared these changes to those induced by other viral, bacterial, and fungal pathogens. There were 1,553 significantly regulated genes with nearly 60% of them down-regulated. MV-infected DCs up-regulated a core of genes associated with maturation of antigen-presenting function and migration to lymph nodes but also included genes for IFN-regulatory factors 1 and 7, 2'5' oligoadenylate synthetase, Mx, and TNF superfamily proteins 2, 7, 9, and 10 (TNF-related apoptosis-inducing ligand). MV induced genes for IFNs, ILs, chemokines, antiviral proteins, histones, and metallothioneins, many of which were also induced by influenza virus, whereas genes for protein synthesis and oxidative phosphorylation were down-regulated. Unique to MV were the induction of genes for a broad array of IFN-alphas and the failure to up-regulate dsRNA-dependent protein kinase. These results provide a modular view of common and unique DC responses after infection and suggest mechanisms by which MV may modulate the immune response.

[Relationship between cytotoxicity of two types of TNF-alpha and intracellular free calcium concentration in target cells].

AIM: To compare the changes of free calcium concentration in target cells killed by transmembrane tumor necrosis factor-alpha(TM-TNF-alpha) and secretory TNF-alpha(S-TNF-alpha). METHODS: The cytotoxicity of two types of TNF-alpha was tested by bioassay. The intracellular Ca(2+) concentration was determined by Frua-2. RESULTS: TM-TNF-alpha had cytotoxic effect on all 6 kinds of target cells, whereas S-TNF-alpha could kill only two of them. The cytotoxic activity of both types of TNF-alpha was accompanied by a dramatically increase of intracellular free Ca(2+) concentration. The intracellular Ca(2+) concentration in the target cells treated with S-TNF-alpha was obviously reduced by pretreating target cells with 10 micromol/L calcium chelator EGTA for 30 minutes (P<0.01) and the cytotoxicity of S-TNF-alpha was significantly inhibited (P<0.01), while the pretreatment with EGTA had no effect on the intracellular Ca(2+) concentration in the target cells treated with TM-TNF-alpha and the cytotoxicity of TM-TNF-alpha. CONCLUSION: These results suggest that both types of TNF-alpha increase Ca(2+) concentration in target cells by promoting the redistribution of intracellular free calcium and only S-TNF-alpha seems to be able to accelerate the influx of extracellular calcium into the target cells.

[The relationship of p53 and the cytotoxicity mediated by TM-TNF-alpha and S-TNF-alpha].

AIM: To explore the relationship of p53 and the cytotoxicity mediated by TM-TNF-alpha and S-TNF-alpha. METHODS: P53 mutation in tumor cell was detected by PCR-SSCP. Wide type p53 expression plasmid was transfected to tumor cells with mutant p53 gene, while the mutant type p53 plasmid to tumor cell with wide type p53 gene.Then,the effects of transfection on the cytotoxicity of two types of TNF were detected. RESULTS: Mutation in the p53 gene were found in most of tumor cells (Raji, HL-60, K562) which were resistant to S-TNF-alpha. The tumor cells transfected with wild type p53 plasmid were more sensitive to S-TNF-alpha while the tumor cells transfected with mutant type p53 plasmid were less sensitive to S-TNF-alpha. But the cytotoxicity of TM-TNF-alpha was not affected by the transfection. CONCLUSION: The cytotoxicity mediated by TM-TNF-alpha is not dependent on wide type p53, which may account for the broader tumorcidal spectrum of TM-TNF-alpha than that of S-TNF-alpha.

Tumor necrosis factors.

Since the discovery of tumor necrosis factor (TNF) and lymphotoxin, many structurally related factors have been elucidated in mammals that are grouped together in the TNF Ligand Superfamily. These factors have profound pleiotropic roles involving inflammation, apoptosis, cell proliferation and stimulation of the immune system. TNF has only been isolated from mammals and fish. While two TNFs (alpha and beta) are present in mammals, it appears that only one form of TNF is found in fish that is more similar in structure and genomic organization to mammalian TNFalpha. TNF transcripts are expressed in both mammals and fish with similar kinetics, and the involvement of NF-kappaB in TNF expression in fish suggests that transcriptional regulation may be similar within vertebrates. Mammalian TNFalpha stimulates macrophage activity in fish and birds, and in both groups of vertebrates, macrophage-derived supernatants have been shown to contain TNF-like activities, suggesting the presence of bioactive native TNFalpha.

Epithelial inflammation response induced by Shigella flexneri depends on mucin gene expression.

The protective effects of different mucin gene profiles on gut protection were assessed by the evaluation of TNFalpha production by intestinal epithelial cells infected by Shigella flexneri. Three HT-29 cell lines were used: HT29-G(-) (enterocyte-like cells, secreting no mucins), HT29-FU (highly expressing MUC2 and MUC4) and HT29-MTX (highly expressing MUC3 and MUC5AC). These cells were infected either by an invasive (M90T) or the control isogenic (BS176) strains of S. flexneri, and TNFalpha mRNA production was quantified by competitive PCR. In the HT29-G(-) cells, M90T induced an increased production of TNFalpha mRNA compared to BS176, giving a TNFalpha ratio of 5.6 +/- 3.3. In contrast, similar levels of TNFalpha mRNA were detected in HT29-FU and HT29-MTX cells stimulated with either M90T or BS176, giving ratios of 1.4 +/- 1.3 and 1.0 +/- 0.1, respectively. The results suggest that mucin genes have abilities to protect epithelial cells against S. flexneri. Furthermore, the difference in the TNFalpha ratio between the HT29-FU and HT29-MTX cells suggests distinct protective effects for these two mucin-secreting epithelial cells.

Molecular cloning and characterization of beluga whale (Delphinapterus leucas) interleukin-1beta and tumor necrosis factor-alpha.

Interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) are cytokines produced primarily by monocytes and macrophages with regulatory effects in inflammation and multiple aspects of the immune response. As yet, no molecular data have been reported for IL-1beta and TNF-alpha of the beluga whale. In this study, we cloned and determined the entire cDNA sequence encoding beluga whale IL-1beta and TNF-alpha. The genetic relationship of the cytokine sequences was then analyzed with those from several mammalian species, including the human and the pig. The homology of beluga whale IL-1beta nucleic acid and deduced amino acid sequences with those from these mammalian species ranged from 74.6 to 86.0% and 62.7 to 77.1%, respectively, whereas that of TNF-alpha varied from 79.3 to 90.8% and 75.3 to 87.7%, respectively. Phylogenetic analyses based on deduced amino acid sequences showed that the beluga whale IL-1beta and TNF-alpha were most closely related to those of the ruminant species (cattle, sheep, and deer). The beluga whale IL-1beta- and TNF-alpha-encoding sequences were thereafter successfully expressed in Escherichia coli as fusion proteins by using procaryotic expression vectors. The fusion proteins were used to produce beluga whale IL-1beta- and TNF-alpha-specific rabbit antisera.

Proposed standard nomenclature for new tumor necrosis factor family members involved in the regulation of bone resorption. The American Society for Bone and Mineral Research President's Committee on Nomenclature.

Recently, three new family members of the tumor necrosis factor (TNF) ligand and receptor signaling system that play a critical role in the regulation of bone resorption have been identified and cloned. These also have been shown to play an important role in regulating the immune system. A proliferation of synonyms for these molecules has led to miscommunication and redundancy. To resolve this, the President of the American Society for Bone and Mineral Research (ASBMR) appointed a special committee to recommend a standard nomenclature. After considerable deliberation and after vetting by workers in the field, the Committee recommends the names of receptor activator of NF-kappaB (RANK) for the membrane receptor, RANK ligand (RANKL) for the ligand, and osteoprotegerin (OPG) for the decoy receptor.

Subtyping for TNFa microsatellite sequence variation.

The microsatellite locus TNFa is frequently used as an additional genetic marker in studies of the major histocompatibility complex (MHC). Novel sequence variations at the TNFa locus have been described, and which may have implications for genetic analyses. In this study, we set up a nested polymerase chain reaction-sequence-specific primer (PCR-SSP) approach to type for these TNFa sequence variations. First, sequencing analysis of workshop B lymphoblastoid cell lines (n=13) showed the presence of three sequence variations upstream of the dinucleotide repeat at TNFa. Using nested PCR-SSP, we were able to detect these variations in a larger B lymphoblastoid cell line panel (n=34). Furthermore, we were able to show that TNFa alleles a7 and a10 are present in two distinct conformations leading to "splitting" of TNFa alleles exhibiting identical fragment lengths. To establish the frequency of the TNFa alleles and their variants, we performed microsatellite typing of a large panel of random individuals from the Dutch population (n=272). Subsequent nested PCR-SSP typing showed the presence of three previously described sequence variations in the Dutch population. Furthermore, the presence of a fourth subtype was established. The described variations of allele TNFa7 and TNFa10 are present in the random population with significant frequencies. Haplotyping analysis between HLA-DR, TNFa, and HLA-B showed that allele TNFa7.2 is present in an extended DR7-TNFa7.2-B13 haplotype. In this way, we were able to show that the additional sequence variations behave like distinct TNFa alleles.

Increased TNFA*2, but not TNFB*1, allele frequency in Spanish atopic patients.

Tumor necrosis factor (TNF) is a potent proinflammatory cytokine involved in asthma and atopy. Increased TNF-alpha levels have been found in airway biopsies and bronchoalveolar lavage fluids from asthmatic patients. Constitutional variations in the TNF-alpha secretion levels in vitro are associated with molecular polymorphisms located within and around the TNF loci. Our study objective was to investigate the association between atopy and two described di-allelic polymorphisms in the TNF locus: a G to A transition at position -308 in the 5'-promoter region of the TNFA gene (TNFA*1 and TNFA*2 alleles) and an Ncol restriction fragment length polymorphism (RFLP) in the first intron of the TNFB gene (TNFB*1 and TNFB*2 alleles). The genetic study was performed in 65 unrelated atopic patients and 60 healthy controls. The regions of interest were amplified from genomic DNA using specific primers and polymerase chain reaction. SSP-PCR analysis for TNFA -308 polymorphism genotyping and endonuclease digestion analysis for the TNFB Ncol RFLP were used. The frequency of the TNFA*2 allele was significantly higher in atopic subjects compared to the control group (38.5% vs. 10.5%; chi2 = 32.06; p <0.0001). The TNFA*2 allele is associated with a higher risk for the development of atopy (risk ratio = 9.44; EF = 0.65; chi2 = 30.06 p <0.0005). On the other hand, no significant association between the TNFB alleles and atopy was found. In conclusion, the TNFA*2 allele could be also a genetic risk marker for the predisposition to atopy in our population, as has been reported in other studies. Either the TNFA gene itself or a linked gene on chromosome region 6p21, which has yet to be identified, is a candidate gene for susceptibility to atopy.

Two polymorphisms of the tumour necrosis factor gene do not influence survival in pancreatic cancer.

Polymorphisms of the tumour necrosis factor (TNF) gene have been related to TNF production and outcome in a variety of inflammatory and malignant diseases. Proinflammatory cytokines and the inflammatory state appear to affect outcome in pancreatic cancer. Thus, the present study examined the TNFB and TNF-308 polymorphisms for their relationship to the inflammatory state and survival in pancreatic cancer. Sixty-four patients with advanced pancreatic cancer and 101 healthy subjects were genotyped for each polymorphism. Serum concentrations of the two TNF receptors and C-reactive protein (CRP) were measured in 45 of the cancer patients with no evidence of infection or jaundice, 1 month after surgical intervention. There was no difference in distribution of genotypes between the patient and control groups. There was no association between any genotype and concentrations of any of the measured inflammatory mediators. While those with an elevated CRP concentration had significantly poorer survival, there was no association between either TNF genotype and survival. This study found no association between TNF genotype and the inflammatory state or survival in advanced pancreatic cancer. Other cytokines may be more important than TNF in determining the inflammatory state and disease progress in pancreatic cancer.