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The Babraham Institute Publications database contains details of all publications resulting from our research groups and scientific facilities. Pre-prints by Institute authors can be viewed on the Institute's bioRxiv channel. We believe that free and open access to the outputs of publicly‐funded research offers significant social and economic benefits, as well as aiding the development of new research. We are working to provide Open Access to as many publications as possible and these can be identified below by the padlock icon. Where this hasn't been possible, subscriptions may be required to view the full text.
 

Turner M, Feldmann M Immunology

The expression of the mRNA encoding tumour necrosis factor, lymphotoxin and interleukin-6 by peripheral blood mononuclear cells was analysed. Unstimulated cells contained no detectable mRNA for these cytokines, however each mRNA was transiently expressed after stimulation with either the combination of phytohaemagglutinin and phorbol ester or the single stimulus of lipopolysaccharide. The dual stimulus yielded the stronger signal. The cytokine mRNA's had short half lives, but were stabilised following protein synthesis inhibition. Cyclosporin A completely blocked induction of lymphotoxin and partially inhibited induction of TNF and IL-6 mRNA. The features of regulation described in this paper suggest these genes belong within the "early" set of genes expressed following immune cell activation.

+view abstract Biochemical and biophysical research communications , PMID: 3260492 1988

Turner M, Londei M, Feldmann M Immunology

T cell clones derived from patients with autoimmune diseases were found to be capable of producing tumor necrosis factor (TNF). This was demonstrated by stimulating the clones, in the absence of accessory cells, with antibodies against the Ti/T3 complex and with recombinant interleukin 2 (IL2). Analysis of RNA extracted from these clones showed that TNF mRNA was more abundant than lymphotoxin (LT) mRNA. We also found that TNF protein in the supernatants of these clones was generally more abundant than LT as assessed by using the murine L929 cell assay. TNF production was not limited to T cells from autoimmune individuals, since the T cell tumor HUT78 and T cells purified from the peripheral blood of healthy individuals also made TNF. Unlike the T cell clones, HUT78 produced greater amounts of LT mRNA than TNF mRNA. Induction of TNF mRNA in T cells from healthy individuals displayed a two-signal requirement (phorbol myristate 13-acetate and phytohemagglutinin or OKT3 and phorbol myristate 13-acetate), similar to that described for the induction of the T cell lymphokines IL 2 and interferon-gamma (IFN-gamma). Additionally we found that IL2 alone was sufficient to induce TNF in these cells when they had been precultured with phytohemagglutinin for 7 days to express IL 2 receptors. The cloned T cells we have characterized also produce IFN-gamma which was detected in the supernatants of the clones using a radioimmunoassay. The evidence suggests that T cells can produce TNF and have the potential to deliver by themselves the dual and synergistic signals of TNF/LT and IFN-gamma to target cells, a process which may be of importance in the pathogenesis of human autoimmunity.

+view abstract European journal of immunology , PMID: 3121358 1987

Oxley D,Wilkinson SG Mass Spectrometry

An acidic, partially acetylated galactomannan has been isolated from the lipopolysaccharide of the reference strain (C.D.C. 864-57) for Serratia marcescens serogroup O4. From the results of methylation analysis, Smith degradations, and n.m.r. spectroscopic studies of the O-deacetylated polymer, it was concluded that the repeating unit has the structure shown, in which the acetal-linked pyruvic acid has the R configuration. The polymer is believed to confer O specificity on the organism, but not to constitute the side chain of the lipopolysaccharide. (formula; see text).

+view abstract Carbohydrate research , PMID: 3061646 1988

Grubeck-Loebenstein B, Buchan G, Sadeghi R, Kissonerghis M, Londei M, Turner M, Pirich K, Roka R, Niederle B, Kassal H Immunology

The production and growth regulatory activity of transforming growth factor beta were studied in human thyroid tissue. As estimated by its mRNA expression in fresh tissue samples, transforming growth factor beta was produced in normal and in diseased thyroid glands. Transforming growth factor beta mRNA was mainly produced by thyroid follicular cells and in lesser quantities by thyroid infiltrating mononuclear cells. The concentrations of transforming growth factor beta mRNA were lower in iodine-deficient nontoxic goiter than in Graves' disease and normal thyroid tissue. Transforming growth factor beta protein secretion by cultured thyroid follicular cells was also low in nontoxic goiter, but could be increased by addition of sodium iodide (10 microM) to the culture medium. Recombinant transforming growth factor beta did not affect basal tritiated thymidine incorporation in cultured thyroid follicular cells, but inhibited, at a concentration of 10 ng/ml, the growth stimulatory influence of insulin-like growth factor I, epidermal growth factor, transforming growth factor alpha, TSH, and partly that of normal human serum on cultured thyroid follicular cells. This inhibition was greater in Graves' disease than in nontoxic goiter. These results suggest that transforming growth factor beta may act as an autocrine growth inhibitor on thyroid follicular cells. Decreased transforming growth factor beta production and decreased responsiveness to transforming growth factor beta may be cofactors in the pathogenesis of iodine-deficient nontoxic goiter.

+view abstract The Journal of clinical investigation , PMID: 2921318 1989

Cordingley FT, Bianchi A, Hoffbrand AV, Reittie JE, Heslop HE, Vyakarnam A, Turner M, Meager A, Brenner MK Immunology

Recombinant tumour necrosis factor (TNF) promotes survival and induces proliferation in the tumour cells from two malignancies of B lymphocytes--hairy-cell leukaemia and B-chronic lymphocytic leukaemia. Culture with TNF also induces TNF mRNA and protein, so the cytokine may act as an autocrine tumour growth factor. These growth promoting effects are antagonised by alpha but not by gamma interferon.

+view abstract Lancet , PMID: 2896830 1988

Chantry D, Turner M, Feldmann M Immunology

The effects of interleukin 7 (IL7) previously known as murine pre-B cell growth factor/lymphopoietin 1 on the growth of murine thymocytes was investigated. In the presence of a suboptimal dose of phytohemagglutinin, IL7 induced a dose-dependent increase in thymocyte proliferation which was comparable to that induced by IL1. Additionally IL7 was shown to synergize with a suboptimal dose of IL1 to enhance thymocyte proliferation. Thymocyte proliferation induced by IL7, like that induced by IL1, was inhibited when either recombinant transforming growth factor (TGF) beta 1 or beta 2 were added at the initiation of culture. Interestingly, IL7-driven thymocyte proliferation was considerably less susceptible to inhibition by TGF-beta 1 or TGF-beta 2 than that induced by IL1. Taken together these results suggest IL7 may activate distinct populations of thymocytes and/or act through a pathway distinct from that utilized by IL1.

+view abstract European journal of immunology , PMID: 2786474 1989

Kendrick KM, De la Riva C, Hinton M, Baldwin BA

Concentrations of monoamines and metabolites and amino acids were measured in microdialysis samples taken from the medial preoptic area of 5 conscious sheep before, during and after exposure to an ambient temperature of 45 degrees C. Concentrations of dopamine, noradrenaline and aspartate significantly increased, and those of the serotonin metabolite, 5-hydroxyindole-3-acetic acid (5-HIAA), significantly decreased during heat exposure and although panting was induced, body temperature did not change. Concentrations of noradrenaline and aspartate declined and 5-HIAA increased to preheat exposure levels during the 60 min after the ambient temperature was reduced but levels of dopamine and its metabolite, homovanillic acid, remained elevated. Dopamine, noradrenaline, 5-HIAA and aspartate concentrations were not significantly altered by isolation stress and did not show significant changes in the cortex following heat exposure. These experiments provide further support for the proposed roles of dopamine, noradrenaline, serotonin and aspartate in the neural control of autonomic thermoregulatory responses.

+view abstract Brain research bulletin , PMID: 2713726

Oxley D,Wilkinson SG Mass Spectrometry

The putative O-specific polysaccharide for Serratia marcescens serogroup O24 is a galactan with a branched, trisaccharide repeating-unit of the structure shown. The structure of the backbone is identical to that of the linear galactans isolated from the reference strains for S. marcescens serogroups O16 and O20, presumably accounting for the serological cross-reactions observed. (Formula: see text)

+view abstract Carbohydrate research , PMID: 2699831 1989

Oxley D,Wilkinson SG Mass Spectrometry

A neutral polymer (the putative O antigen) has been isolated from the lipopolysaccharide of the reference strain for Serratia marcescens serogroup 018. From the results of spectroscopic and degradative studies, the repeating unit of the polymer was identified as a linear tetrasaccharide having the structure shown. ----2)-alpha-L-Rhap-(1----2)-alpha-L-Rhap-(1----6)-alpha-D- GlcpNAc-(1----

+view abstract Carbohydrate research , PMID: 2699830 1989

Oxley D,Wilkinson SG Mass Spectrometry

Neutral polymers have been isolated from the lipopolysaccharides of the reference strains for Serratia marcescens O16 and O20, serogroups which exhibit significant cross-reactivity. Both organisms produce a galactan with the disaccharide repeating-unit shown, and which apparently accounts for the serological observations. The same galactan has also been reported as the O4-specific polysaccharide of Pasteurella haemolytica. In S. marcescens O16, the galactan is apparently accompanied by a polymer of 2-substituted beta-D-ribofuranosyl residues.

+view abstract Carbohydrate research , PMID: 2692814 1989

Grubeck-Loebenstein B, Buchan G, Chantry D, Kassal H, Londei M, Pirich K, Barrett K, Turner M, Waldhausl W, Feldmann M Immunology

Cytokine production was studied in thyroid tissue from patients with Graves' disease, Hashimoto's thyroiditis and non-toxic goitre. The expression of interferon gamma, tumour necrosis factor alpha and beta, interleukin-1 alpha and beta, interleukin-6 and platelet-derived growth factor A chain was assessed by slot-blot analysis of the respective mRNA in freshly isolated tissue samples. All seven cytokines were detected in patients of all groups. Although the respective mRNA levels were, in general, higher in thyroid autoimmune disorders, this appeared to relate to the degree of the lymphocytic infiltration of the thyroid gland at the time of surgery. Purified thyroid follicular cells expressed high levels of interleukin-1 alpha and interleukin-6 mRNA and when established in primary culture, purified thyroid follicular cells from Graves' disease as well as non-toxic goitre produced interleukin-1 alpha and interleukin-6 bioactivity spontaneously. In the case of interleukin-1 this could be further augmented by addition of lipopolysaccharide to the thyroid follicular cell cultures. These results demonstrate that the lymphocytic infiltrate found in autoimmune and non-autoimmune thyroid disorders is associated with cytokine production. Additionally we have shown that intrathyroidal cytokine production is not restricted to thyroid-infiltrating mononuclear cells, but may also involve thyroid follicular cells both in vivo and in vitro. The cytokines produced by thyroid follicular cells may have an important role in stimulating autoantigen specific T cells in vivo as both interleukin-1 and interleukin-6 facilitate T cell activation.

+view abstract Clinical and experimental immunology , PMID: 2680182 1989

Oxley D,Wilkinson SG Mass Spectrometry

Both neutral and acidic polymers have been isolated from the lipopolysaccharide extract of the reference strain (C.D.C. 4523-60) for Serratia marcescens serogroup O15. By means of n.m.r. spectroscopy, methylation analysis, and studies of degradation products, the acidic polysaccharide was shown to have a branched pentasaccharide repeating-unit with the following structure. (Formula: see text)

+view abstract Carbohydrate research , PMID: 2660988 1989

Duncombe AS, Heslop HE, Turner M, Meager A, Priest R, Exley T, Brenner MK Immunology

Autocrine production of growth factors may contribute to the rapid and fatal proliferation of acute hematologic malignancies. We have investigated whether the more controlled growth of less aggressive malignancies such as chronic myeloid leukemia (CML) may be associated with autocrine production of growth inhibitory factors. TNF inhibits the growth of both normal and leukemic hemopoietic progenitor cells. We find that exogenous TNF reduces the viability and DNA synthesis of purified myeloid cells from patients with CML and inhibits myeloid colony formation by patient progenitor cells. However, unlike progenitor cells from normal donors, patient myeloid progenitor cells also constitutively express mRNA for TNF and secrete functional TNF protein in culture. This endogenous TNF impedes the growth of CML cells because anti-TNF mAb shown to neutralize bioactive human TNF increases CML cell DNA synthesis whereas non-neutralizing anti-TNF mAb has no effect. Production of TNF by CML cells is not associated with production of lymphotoxin (TNF-beta), IL-1 or IL-6. TNF-mediated autocrine growth inhibition may contribute to the maintenance of the stable, chronic phase of this disease and similar mechanisms may operate in other malignancies to limit tumor proliferation. Competition between autocrine growth promoting and inhibiting factors may underlie the observed differences in biologic behavior between acute and chronic malignancies.

+view abstract Journal of immunology (Baltimore, Md. : 1950) , PMID: 2584719 1989

Chantry D, Turner M, Abney E, Feldmann M Immunology

Transforming growth factor-beta 1 (TGF-beta 1) is one of a family of polypeptides involved in the regulation of cell growth and differentiation. The effects of human rTGF-beta 1 on the production of IL-1 and TNF by activated PBMC were studied. The addition of TGF-beta 1 alone caused an increase in the levels of mRNA for IL-1 alpha, IL-1 beta, and TGF-alpha. This was due to increased transcription rather than enhanced mRNA stability. The induced mRNA were of the appropriate size as assessed by Northern blotting. However, the mRNA did not appear to be translated into protein, inasmuch as the translation products of IL-1 beta and TNF-alpha were not detected by RIA or ELISA. Furthermore, in experiments utilizing a neutralizing antibody to TGF-beta 1, we were unable to unmask IL-1 biologic activities and unable to detect TNF biologic activity in the WEHI 164 cytotoxicity assay. TGF-beta inhibited in a dose-dependent manner the induction of IL-1 beta by LPS or TNF but not by PHA and PMA. Similarly, LPS induction of TNF-alpha was blocked by TGF-beta, whereas induction of PMA and PHA was completely resistant. TGF-beta 1 did not increase PGE2 secretion or cause elevated intracellular cAMP; thus, the inhibitory effects of TGF-beta 1 seem not to be mediated by PGE2 or cAMP, which have both been implicated in post-transcriptional control of cytokine gene expression. These findings suggest a dual role for TGF-beta 1 in the regulation of cytokine production at both transcriptional and translational levels.

+view abstract Journal of immunology (Baltimore, Md. : 1950) , PMID: 2542408 1989

Colombo C, Nobili P, Giussani GA, Crosta C, Ronchi O, Alloni R Signalling

The Authors report their experience about 20 patients operated on since 1975 for primary carcinoma of the gallbladder. They remark their disappointment because of the poor percentage of preoperative and early diagnosis, that only allows a radical surgical therapy. More attention, therefore, should be payed to this not so rare pathology in the hope the survival of the patients radically operated will increase.

+view abstract Il Giornale di chirurgia , PMID: 2518295 1989

Turner M, Chantry D, Buchan G, Barrett K, Feldmann M Immunology

IL-1 gene expression was investigated in human blood mononuclear cells. IL-1 alpha and IL-1 beta mRNA were induced with LPS or TNF. Kinetic measurements on Northern blots revealed that these stimuli elicited qualitatively similar changes in IL-1 mRNA levels, and that expression of IL-1 mRNA was transient. IL-1 beta mRNA was the predominant mRNA species and remained elevated for somewhat longer than IL-1 alpha mRNA. TNF and IFN-gamma synergized to induce both species of IL-1 mRNA and IL-1 bioactivity. Transcriptional control, as measured by nuclear run on assays, partly determines the greater levels of IL-1 beta mRNA because the rate of IL-1 beta transcription was greater than that of IL-1 alpha. Cycloheximide (CHX) was able to induce IL-1 mRNA but did not induce transcription of either IL-1 gene. When added to cultures pretreated with TNF or LPS, CHX superinduced IL-1 mRNA, but IL-1 transcription was not increased. If added simultaneously CHX blocked TNF-induced IL-1 gene transcription, suggesting that TNF may induce factors required for IL-1 gene transcription. CHX increased the stability of both IL-1 alpha and IL-1 beta mRNA, demonstrating the existence of a post-transcriptional form of control. In half-life experiments IL-1 beta mRNA was more stable than IL-1 alpha mRNA, indicating that post-transcriptional control also contributes to the greater steady state levels of IL-1 beta. Taken together, the available evidence suggests IL-1 alpha and IL-1 beta mRNA are regulated differentially at both the transcriptional and post-transcriptional level.

+view abstract Journal of immunology (Baltimore, Md. : 1950) , PMID: 2511244 1989

Portillo G, Turner M, Chantry D, Feldmann M Immunology

The monocytic tumour, THP-1, expresses many of the properties of monocytes, both by cell surface staining and its capacity to produce monokines. It was used as a source of homogenous monocytic cells as a model to determine whether a variety of highly purified or recombinant cytokines could induce HLA-DR expression and the production of interleukin-1 (IL-1). Interferon-gamma (IFN-gamma) alone induced HLA-DR. Tumour necrosis factor (TNF), lymphotoxin (LT) and granulocyte-macrophage colony-stimulating factor (GM-CSF) alone were able to induce IL-1 but not HLA-DR. When IFN-gamma was combined with TNF, induction of HLA-DR and IL-1 was enhanced in a synergistic manner. These effects were detectable at a pretranslational level as synergistic effects were observed on DR alpha mRNA and IL-1 beta mRNA levels. The results demonstrate the specificity of IFN-gamma as the inductive stimulus for HLA-DR expression by THP-1 cells. As IFN-gamma and TNF are products of activated T cells, the synergistic role for these molecules in macrophage activation is discussed.

+view abstract Immunology , PMID: 2494105 1989

Oxley D,Wilkinson SG Mass Spectrometry

A neutral glucorhamnan has been isolated from the lipopolysaccharide of the O10 reference strain (C.D.C. 1287-54) of Serratia marcescens. By means of n.m.r. spectroscopy, methylation analysis, and degradative studies, the polymer (the putative O-specific antigen) was found to have the branched, pentasaccharide repeating-unit shown. (formula; see text).

+view abstract Carbohydrate research , PMID: 2472885 1989

Oxley D,Wilkinson SG Mass Spectrometry

A partially acetylated acidic galactoglucomannan has been isolated from the lipopolysaccharide of the O3 reference strain (C.D.C. 863-57) of Serratia marcescens. By means of n.m.r. spectroscopy, methylation analysis, and degradative studies, the polymer was found to have the branched pentasaccharide repeating-unit shown. The position(s) of partial acetylation were not determined. Although the polymer is believed to confer O specificity on the parent organism, it is probably not an integral component of the lipopolysaccharide. (Formula: see text).

+view abstract Carbohydrate research , PMID: 2472884 1989

Hirano T, Matsuda T, Turner M, Miyasaka N, Buchan G, Tang B, Sato K, Shimizu M, Maini R, Feldmann M Immunology

High levels of interleukin 6 (IL 6/B cell stimulatory factor-2) were detected in synovial fluids from the joints of patients with active rheumatoid arthritis (RA). The cells found in freshly isolated synovial fluid constitutively expressed IL 6 mRNA. The synovial tissues obtained by joint biopsy were also found to produce IL 6 in vitro. Immunohistochemical analysis demonstrated that CD2+ T cells as well as CD20+ blastoid B cells in the synovial tissues produce IL 6. The data indicate that IL 6 is generated constitutively in RA and its overproduction may explain the local as well as the generalized symptoms of RA, since IL 6 can function as B cell growth and differentiation factor as well as hepatocyte-stimulating factor.

+view abstract European journal of immunology , PMID: 2462501 1988

Oxley D,Wilkinson SG Mass Spectrometry

Structural studies have been carried out on the O-specific polysaccharide from the lipopolysaccharide of the reference strain (CDC 1604-55) for serogroup O8 of Serratia marcescens. The polymer has a branched, tetrasaccharide repeating unit of D-galactose(Gal),D-glucose(Glc), and 2-acetamido-2-deoxy-D-glucose(GlcNAc) with the following structure: (Formula: see text). The anomeric configuration assigned to the glucose residue differs from that (beta) previously proposed [Tarcsay, L., Wang, C. S., Li, S.-C. and Alaupovic, P. (1973) Biochemistry 12, 1948-1955]. The structure of the O8 polymer is identical with that of one of two polymers present in the cell envelope of a strain (CDC 1783-57) of S. marcescens O14.

+view abstract European journal of biochemistry / FEBS , PMID: 2422032 1986

Oxley D,Wilkinson SG Mass Spectrometry

Both a neutral and an acidic polymer have been isolated from a lipopolysaccharide extract of the reference strain for Serratia marcescens serogroup O22. The neutral polymer has a linear structure with the repeating unit shown. The same tetrasaccharide unit also forms the backbone of the branched neutral polymer isolated from the reference strain for serogroup O10, which cross-reacts strongly with O22. ----2)-alpha-L-Rhap-(1----2)-alpha-L-Rhap-(1----3)-alpha-L-+ ++Rhap-(1----3)-alpha- D-GlcpNAc-(1----

+view abstract Carbohydrate research , PMID: 2276124 1990

Heslop HE, Bianchi AC, Cordingley FT, Turner M, Chandima W, De Mel CP, Hoffbrand AV, Brenner MK Immunology

The B lymphoproliferative disorders B chronic lymphocytic leukemia (B-CLL) and hairy cell leukemia (HCL) produce a number of autocrine growth factors, including tumor necrosis factor (TNF), interleukin 6 (IL-6), and IL-1, all of which may induce positive feedback growth loops. If such malignancies depend on these autocrine growth loops for survival, their interruption may be therapeutically valuable. Interferon alpha (IFN-alpha) abrogates TNF- or IL-6-induced proliferation of HCL and B-CLL cells in vitro and has therapeutic activity in these diseases. We have investigated the possibility that IFN-alpha may act by interrupting autocrine growth factor loops. If purified B-CLL or HCL cells are cultured in the presence of TNF, there is induction of mRNA for TNF, IL-1 alpha, IL-1 beta, and IL-6. However, culture in the presence of IFN-alpha in addition to TNF reduced the level of mRNA for all these cytokines, compared with cells cultured in TNF alone. While cytokine mRNA levels were diminished, levels of mRNA for the ribonuclease activator 2-5A synthetase were increased. Analysis of the kinetics of cytokine mRNA production showed that levels fall shortly after the rise of 2-5A synthetase mRNA. IFN-alpha may produce these effects by shortening the half-life of cytokine mRNA, since TNF mRNA half-life in B-CLL and HCL cells is substantially reduced when the cells are cultured with IFN-alpha. These data suggest that IFN-alpha may mediate its therapeutic effects in these malignancies by blocking autocrine growth factor loops.

+view abstract The Journal of experimental medicine , PMID: 2258703 1990