Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.1.1.17 (ornithine decarboxylase)
6,351 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histamine and putrescine (a precursor of polyamines) are formed by histidine decarboxylase (HDC) and ornithine decarboxylase (ODC), respectively. Within a few hours after injection of a lipopolysaccharide (LPS) into mice, HDC is induced in the liver, spleen, lung and bone marrow, and ODC is induced in the liver, spleen and bone marrow. Since LPS is known to stimulate the production of various cytokines, the abilities of various cytokines to induce HDC and ODC in the tissues of mice were examined. IL-2, IL-6, IL-8, IFN gamma and M-CSF were ineffective. IL-1 alpha, IL-1 beta, TNF alpha and TNF beta induced HDC and ODC, as does LPS. On the other hand, GM-CSF and G-CSF induced HDC and ODC only in the spleen and bone marrow within a few hours after their injection. These results suggest that, in addition to their roles in inflammation or immune responses, HDC and ODC are also involved in an early stage of hematopoiesis.
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PMID:GM-CSF and G-CSF stimulate the synthesis of histamine and putrescine in the hematopoietic organs in vivo. 138 20

DL-alpha-Difluoromethylornithine (DFMO) is a specific inhibitor of the rate-limiting enzyme in polyamine biosynthesis, ornithine decarboxylase (ODC). DFMO (1 mM) added to C57BL/6 anti-DBA/2 murine mixed lymphocyte cultures (MLC) inhibited cytolytic T lymphocyte (CTL) activity on days 3 and 5 by 88% and 96%. Putrescine (PUT; 1 mM) and spermidine (SPD; 0.01 mM) reversed DFMO inhibition, indicating that DFMO inhibition was caused by ODC antagonism. T helper (Th) cell and accessory cell functions were not affected since DFMO did not inhibit MLC proliferation or lymphokine production. Furthermore, exogenous IL-1, IL-2, IL-4, interferon-gamma, or a rat Con A supernatant failed to abrogate DFMO inhibition. Inhibition was reversible within 48 h of removing cells from DFMO; moreover, subsequent development of DFMO-blocked CTL did not require CD4+ cells. Clonal expansion of CTL treated with 1 mM DFMO for three days in MLC, determined by subsequent analysis in limiting dilution microcultures, was only approx. 1 cell division less than control. These results indicate DFMO inhibition is exerted directly on the CTL, and that the process of differentiation was more affected by a reduction in polyamine biosynthesis than proliferation. This may be a useful model to the study stages and events of CTL development, and the roles played by polyamines in supporting these processes.
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PMID:Difluoromethylornithine (DFMO) arrests murine CTL development in the late, pre-effector stage. 183 10

Haemopoietic growth factors stimulate a number of common biochemical and molecular events despite the high specificity of individual ligand-receptor interactions. Analysis of three distinct colony-stimulating factors (CSFs), interleukin 3 (IL-3), granulocyte-CSF and granulocyte macrophage-CSF, and the lymphocytotropic growth factor IL-2 revealed remarkably similar distal subcellular biochemical signals, although the mode of initial membrane signal transduction may differ significantly. Both early progenitor cell growth factors, such as IL-3, and late-acting factors, such as CSF-1, stimulate tyrosine and serine/threonine substrate phosphorylations. One substrate (p68) is phosphorylated in response to many CSFs and to IL-2, suggesting that it plays a highly conserved role in the signal transduction processes of many different receptor(s). The proliferative CSFs and IL-2 also stimulate the expression of many of the same genes, including protooncogenes, the ornithine decarboxylase gene, and members of the phylogenetically ancient family of stress response genes. Thus although initial membrane events may differ among the proliferative stimulants, the biochemical and molecular convergence of signalling pathways on highly conserved cellular substrates and on the programme of gene expression is seen.
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PMID:Haemopoietic growth factor regulation of protein kinases and genes associated with cell proliferation. 218 Jun 44

IL-2 regulates the expression and activation of the principal rate-limiting enzyme of polyamine synthesis, ornithine decarboxylase (ODC). The apparent activation of ODC occurs by two independent steps. Rapid activation of enzyme occurs within the first 10 min of lymphokine treatment of cloned IL-2-dependent murine cell lines. The initial rapid rise in enzyme activity is insensitive to protein or mRNA synthesis inhibitors. The early rise in ODC activity is followed by a protracted increase in enzyme activity, apparent protein measured by [3H]difluoromethylornithine binding, and by accumulation of steady state ODC mRNA. Stable analogues of cAMP which inhibit IL-2-stimulated proliferation, suppressed only the mRNA-dependent increase in ODC activity. Phorbol esters were shown to increase steady state levels of ODC mRNA whereas cAMP analogue clearly inhibited the growth factor-induced increase in ODC mRNA. These studies show that IL-2 regulates the expression of ODC at multiple levels, including transcription and accumulation of steady state mRNA, and post-translational activation of an enzyme important for DNA synthesis. Furthermore, anti-proliferative signals such as cAMP may effect the regulation of ODC enzyme production at the level of mRNA accumulation and stability.
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PMID:Regulation of ornithine decarboxylase activity by IL-2 and cyclic AMP. 284 Apr 61

The objective of the present investigation was to evaluate the requirement for increased ornithine decarboxylase (ODC) activity and polyamine biosynthesis in the induction of cytolytic T lymphocytes (CTL). In this regard, we have utilized alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC. DFMO treatment completely abrogated Con A-induced NW T-cell ODC activity. Similarly, DFMO treatment reduced putrescine and spermidine biosynthesis 100 and 87% respectively by the end of a 48-hr incubation period. Polyamine depletion reduced the Con A-mediated polyclonal induction of CTL by 52 and 81% at 24 and 48 hr of culture, respectively. The effect of DFMO on CTL induction could be reversed by the addition of exogenous putrescine. These data indicate that the observed effects of DFMO on CTL induction were mediated through inhibition of polyamine biosynthesis. Therefore, increased ODC activity and polyamine biosynthesis are required for optimal CTL induction. Furthermore, polyamine depletion did not impair IL-2 production; however, IL-2-dependent proliferation was reduced. These data are the first to discriminate between the requirement for polyamines with regard to IL-2 responsiveness, rather than IL-2 production, during a primary T-cell mitogenic response.
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PMID:Increased ornithine decarboxylase activity and polyamine biosynthesis are required for optimal cytolytic T lymphocyte induction. 310 80

Haemopoietic growth factors stimulate a number of consensus biochemical and molecular events regardless of the specificity detailed by unique ligand and receptor structures. Analysis of three distinct colony stimulating factors, CSFs (IL-3, G-CSF, GM-CSF) and the lymphocytotropic growth factor IL-2 reveal remarkable similar distal subcellular biochemical signals although initial membrane 'signal transduction' may differ significantly. Both early progenitor cell growth factors, such as IL-3, and late acting factors such as CSF-1, stimulate tyrosine and serine-threonine substrate phosphorylations. One substrate (p68) is phosphorylated by many CSF stimulants, including IL-2, suggesting a highly conserved role in many unique receptor(s) signal transduction processes. The proliferative CSFs and IL-2 also stimulate the expression of many of the same genes including proto-oncogenes, ornithine decarboxylase and members of the ancient family of stress response genes. Although initial membrane events may differ among the respective proliferative stimulants, biochemical and molecular convergence on highly conserved cellular substrates and the programme of gene expression is seen.
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PMID:Molecular events associated with the action of haemopoietic growth factors. 327 Apr 54

Ornithine decarboxylase (ODC) is the initial enzyme in polyamine synthesis. An increase in ODC activity is associated with increased RNA, DNA, and protein synthesis. We have used the induction of ODC by mitogens and alloantigens in human peripheral blood lymphocytes as an intracellular marker of protein synthesis and lymphocyte activation. The immunosuppressive agent cyclosporine was found to inhibit both the mitogen and alloantigen stimulated induction of ODC in lymphocytes in a manner that parallels inhibition of subsequent 3H-thymidine incorporation. When purified T lymphocytes were stimulated with mitogen alone, minimal ODC activity was detected. The addition of 5% monocytes, human Interleukin-1 (IL-1), or T cell growth factor (IL-2) enhanced mitogen-induced ODC activity in T lymphocytes 4-10-fold. Cyclosporine inhibited the induction of ODC when T lymphocytes were combined with monocytes or growth factors. We conclude that (1) the induction of ODC in human lymphocytes by mitogen and alloantigen is inhibited in the presence of cyclosporine; (2) the induction of ODC activity in purified T lymphocytes requires the presence of both mitogen and monocytes or their products; (3) IL-1 and IL-2 can supplement for monocytes and augment the phytohemagglutinin induction of ODC in T lymphocytes; and (4) cyclosporine inhibits ODC induction in T lymphocytes stimulated with mitogen in the added presence of monocytes, IL-1, or IL-2. The inhibition of ODC induction and polyamine synthesis by cyclosporine adds insight into its mode of action on the mechanisms involved in early T cell activation.
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PMID:The effect of cyclosporine on ornithine decarboxylase induction with mitogens, antigens, and lymphokines. 623 49

FK-506 and cyclosporine A (CsA) are two immunosuppressive drugs used in the treatment of patients after liver and small intestine transplantation. A clinical advantage of FK-506 over CsA has been observed in these patients. Although the immunomodulation of both drugs has been well documented in the circulatory immune system, their effect on the mucosal immune system is not well established. In this study, the effect of FK-506 on the human gut mucosal immune system was compared to CsA. Proliferation of human colonic lamina propria lymphocytes (LPL) was measured by DNA synthesis and ornithine decarboxylase (ODC) activity. Results show that FK-506 and CsA suppress LPL DNA proliferation in a dose-dependent manner. FK-506 had a stronger antiproliferative effect compared to CsA. Moreover, the antiproliferative effect of both drugs was not dependent on monocytes or monocyte-associated factors (IL-1 beta, IL-6). In addition, exogenous addition of IL-2 did not restore the suppressive effect of either drug on LPL DNA synthesis. We conclude that: (1) both drugs have an antiproliferative effect on the human mucosal immune system; and (2) the stronger effect of FK-506 on human LPL compared to CsA may explain its superior clinical response observed in patients after liver/small intestine transplantation.
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PMID:FK-506 and cyclosporine A (CsA) immunomodulation of the human gut mucosal immune system. 755 46

Zeng Sheng Pin Pian (ZSPP) is a mixture of medicinal herbs which has been shown to be effective in the secondary prevention of esophageal cancer in a high-risk area among a population with severe esophageal dysplasia. This study in mice aimed at elucidating the possible mechanism of the cancer-preventing activity of ZSPP. The results indicate that ZSPP is a good biologic response modifier (BRM) as shown by its enhancing effects on lymphocyte blastogenesis, IL-2 secretion, NK cell activity, delayed-type hypersensitivity reaction to DNCB, hemolysin response to SRBC and the phagocytic function of the reticulo-endothelial system. While ZSPP did not inhibit the growth of S-180 in mice, it exhibited significant inhibitory effect on ornithine decarboxylase (ODC) activity induced by the application of croton oil to the skin. Taken together, the immune enhancing activity and the anti-tumor-promoting activity of ZSPP could explain, at least in part, its efficacy in the prevention of esophageal cancer among high-risk people with precursor dysplastic lesions.
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PMID:[Experimental study on the pharmacologic effects of zeng sheng pin pian]. 772 Apr 95

Budesonide, a beta-adreno-receptor agonist, is comparable to corticosteroid in the treatment of patients with inflammatory bowel disease with the advantage of minimal side effect. Although the immunomodulatory effects of budesonide on the circulatory and respiratory mucosal immune system have been reported, its effect on the human gut immune system has not been published. In this study, the effect of budesonide on the human gut immune system was compared to methyl-prednisolone. The cellular immune function was measured in-vitro by DNA synthesis, ornithine decarboxylase (ODC) activity and TNFalpha secretion. We found that both drugs have a comparable inhibitory effect on DNA synthesis, ODC activity and suppression of TNFalpha secretion. Exogenous addition of IL-2, did not restore the antiproliferative effect of both drugs. We conclude that budesonide has a comparative suppressive effect to methyl-prednisolone on the gut immune system which is not related to IL-2 secretion. The antiproliferative response may explain the therapeutic effect of budesonide on patients with inflammatory bowel disease.
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PMID:Immunosuppressive effect of budesonide on human lamina propria lymphocytes. 950 28


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