Symptom courses during and after psychotherapy: models and simulations
Interleukin-1α/β/receptor antagonist expression during endotoxemia and during endotoxin-initiated...
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THIRD INTERNATIONAL WORKSHOP ON CYTOKINES / 521 427 CHARACTERIZATION OF THE ACTIVATION DOMAIN AND POST- TRANSLATIONAL MODIFICATION OF IL-6DBP NECESSARY FOR INDUCTION OF ACUTE-PHASE GENE TRANSCRIPTION BY IL-6. Dioak P. Ramii. Francois Tronche. Valeria Poli, Gennaro Ciliberto and Riccardo Cortese Istituto di Ricerche di Biologia Molecolare (IRBM), Via Pontina km. 30,600, Pomezia (Rome), Italy The promoter regions of several acute-phase genes contain cis-acting, II-6 dependent responsive elements (IL-6RE) which are both necessary and sufficient for IL-6 dependent transcriptional activation. A family of proteins from hepatoma cell nuclei, which arc characte.rired by the presence of Leucine zipper/basic amino acid DNA binding domain compatible with that of the transcription factor C/EBP, interact with IL-6RE. A cDNA clone for a member of this family, IL-6DBP, has recently been isolated and exhibits strong homology to the c/EBP DNA binding region. Both the DNA binding and trans-activation potential of IL-6DBP are induced by IL-6 in hepatoma cells by a post-translational mechanism. Therefore, IL-6DBP represents the nuclear target for IL-6 signal transduction pathway responsible for transcriptional activation of acute-phase genes. We have used molecular genetic methods to generate systematically altered forms of IL-6DBP and identified several polypeptide segments which are necessary for transcriptional activation. The characteristics of these activations domains and studies that address on the nature of the post-translational modification of IL- 6DBP will be presented. 428 TNF-MEOIATH) DISERSE INTRANGENICMICE: AGEXiElYICMODEL OF ARTHRITIS. L. Prober-t, J. Keffer, H. Cazlaris, S. Georgopmlos, and G. Kollias. Latmatorv of Molecular Genetics, Hellenic Pasteur Inst. 127, Vas..Sofias Ave, 115 21 - Athens, Greece. To analyse the expression of the h- tumm necro- sis factor gene and to fwthur understand its biological function, we generated several trangenic mouse lines car- rying and expressing wild type and recombinant human TNYF gene constructs. We are able to show that andotoxin-rre- spsnsive expression of a wild type human 'INF trangene can be established in trangenic mice. In addition, we can show that its 3'-region is necessary for mcrophage - specific expression. Moreover, we present direct evidence that & B, deregulated expression of a 3'-modified humn TNF trangene leads to the development of chronic inflanmatory @yarthritis in mice and that this outccma can be sup- pressed by administration of mncclonal antibodies against human TNF. Using a different TNF gene construct, we show that T-cell targeted expression of the human TNF transgene induces lymphoid organ- specific pathological abnormalities. while svstemic release of TX? motein in the serum of ;hase mice leads to the da"alo&mt of le- thal vascular throm?msis and tissue necrosis. 429 Interlaukin-lu/P/receptor antagonist Expression during Endotoxemia and during Endotoxin-Initiated Local Acute Inflaxmnation. TR K GUO. S W ES Yi. RC won. SP Eisenbm UC Irvine and Synergen, Inc. During endotoxemia after the i.v. injection of endotoxin (LPS) in the rat, IL-1 a/p mRNA expression peaks at 1 hour in whole organ RNA preparations of the lung, liver, Spl.Z~, and bowel. IL-lra -A peaks at 2 to 4 hours, consistent with the hypothesis that IL-lra acts as an endogenous negative feedback mechanism. After the intratracheal (i.t.) injection of LPS, however, IL-1 and IL-lra rnRNA levels in whole lung peak at 6 hours, concurrent with the maximum influx of neutrophils (PINS) into the bronchoalveolar space. Fractionation of alveolar macrophage-enriched and PM?-enriched sub-populations from bronchoalveolar lavage cells obtained at 6 hours after i.t. injection of LPS confirmed that neutrophils are a source of IL-1 and IL-lra mRNA. The difference in the kinetics of IL-1 and IL-lra mP.NA expression in whole lung RNA preparations after i.v. and i.t. injections of LPS is due to the contribution of PMNs that appear in the lung in large numbers after i.t. injection. Human peripheral blood PMNs were found to express IL-lra mRNA and protein after in vitro incubation with LPS. PMNs can contribute to the up- and down-regulation of their own accumulation by expressing both IL-1 and IL-lra.
Transcript of Interleukin-1α/β/receptor antagonist expression during endotoxemia and during endotoxin-initiated...
THIRD INTERNATIONAL WORKSHOP ON CYTOKINES / 521
427 CHARACTERIZATION OF THE ACTIVATION DOMAIN AND POST- TRANSLATIONAL MODIFICATION OF IL-6DBP NECESSARY FOR INDUCTION OF ACUTE-PHASE GENE TRANSCRIPTION BY IL-6. Dioak P. Ramii. Francois Tronche. Valeria Poli, Gennaro Ciliberto and Riccardo Cortese
Istituto di Ricerche di Biologia Molecolare (IRBM), Via Pontina km. 30,600, Pomezia (Rome), Italy
The promoter regions of several acute-phase genes contain cis-acting, II-6 dependent responsive elements (IL-6RE) which are both necessary and sufficient for IL-6 dependent transcriptional activation. A family of proteins from hepatoma cell nuclei, which arc characte.rired by the presence of Leucine zipper/basic amino acid DNA binding domain compatible with that of the transcription factor C/EBP, interact with IL-6RE. A cDNA clone for a member of this family, IL-6DBP, has recently been isolated and exhibits strong homology to the c/EBP DNA binding region. Both the DNA binding and trans-activation potential of IL-6DBP are induced by IL-6 in hepatoma cells by a post-translational mechanism. Therefore, IL-6DBP represents the nuclear target for IL-6 signal transduction pathway responsible for transcriptional activation of acute-phase genes. We have used molecular genetic methods to generate systematically altered forms of IL-6DBP and identified several polypeptide segments which are necessary for transcriptional activation. The characteristics of these activations domains and studies that address on the nature of the post-translational modification of IL- 6DBP will be presented.
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TNF-MEOIATH) DISERSE INTRANGENICMICE: AGEXiElYICMODEL OF ARTHRITIS. L. Prober-t, J. Keffer, H. Cazlaris, S. Georgopmlos, and G. Kollias. Latmatorv of Molecular Genetics, Hellenic Pasteur Inst. 127, Vas..Sofias Ave, 115 21 - Athens, Greece.
To analyse the expression of the h- tumm necro- sis factor gene and to fwthur understand its biological function, we generated several trangenic mouse lines car- rying and expressing wild type and recombinant human TNYF gene constructs. We are able to show that andotoxin-rre- spsnsive expression of a wild type human 'INF trangene can be established in trangenic mice. In addition, we can show that its 3'-region is necessary for mcrophage - specific expression. Moreover, we present direct evidence that & B, deregulated expression of a 3'-modified humn TNF trangene leads to the development of chronic inflanmatory @yarthritis in mice and that this outccma can be sup- pressed by administration of mncclonal antibodies against human TNF. Using a different TNF gene construct, we show that T-cell targeted expression of the human TNF transgene induces lymphoid organ- specific pathological abnormalities. while svstemic release of TX? motein in the serum of ;hase mice leads to the da"alo&mt of le- thal vascular throm?msis and tissue necrosis.
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Interlaukin-lu/P/receptor antagonist Expression during Endotoxemia and during Endotoxin-Initiated Local Acute Inflaxmnation. TR K GUO. S W
ES Yi. RC won. SP Eisenbm UC Irvine and Synergen, Inc.
During endotoxemia after the i.v. injection of endotoxin (LPS) in the rat, IL-1 a/p mRNA expression peaks at 1 hour in whole organ RNA preparations of the lung, liver, Spl.Z~, and bowel. IL-lra -A peaks at 2 to 4 hours, consistent with the hypothesis that IL-lra acts as an endogenous negative feedback mechanism. After the intratracheal (i.t.) injection of LPS, however, IL-1 and IL-lra rnRNA levels in whole lung peak at 6 hours, concurrent with the maximum influx of neutrophils (PINS) into the bronchoalveolar space. Fractionation of alveolar macrophage-enriched and PM?-enriched sub-populations from bronchoalveolar lavage cells obtained at 6 hours after i.t. injection of LPS confirmed that neutrophils are a source of IL-1 and IL-lra mRNA. The difference in the kinetics of IL-1 and IL-lra mP.NA expression in whole lung RNA preparations after i.v. and i.t. injections of LPS is due to the contribution of PMNs that appear in the lung in large numbers after i.t. injection. Human peripheral blood PMNs were found to express IL-lra mRNA and protein after in vitro incubation with LPS. PMNs can contribute to the up- and down-regulation of their own accumulation by expressing both IL-1 and IL-lra.
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