Mannose 6-, Fructose 1-, and Fructose 6-Phosphates Inhibit Human Natural Cell-Mediated Cytotoxicity
In vitro human natural cell-mediated cytotoxicity (NCMC) to K-562, Molt-4, and F-265 cells is inhibited in a dose-dependent manner by mannose 6-phosphate, fructose 1-phosphate, and fructose 6-phosphate. This inhibition is not observed with mannose, glucose, fucose, glucose 6-phosphate, mannose 1-pho...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 1981-09, Vol.78 (9), p.5797-5801 |
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| creator | Forbes, James T. Bretthauer, Roger K. Oeltmann, Thomas N. |
| description | In vitro human natural cell-mediated cytotoxicity (NCMC) to K-562, Molt-4, and F-265 cells is inhibited in a dose-dependent manner by mannose 6-phosphate, fructose 1-phosphate, and fructose 6-phosphate. This inhibition is not observed with mannose, glucose, fucose, glucose 6-phosphate, mannose 1-phosphate, galactose 1-phosphate, or galactose 6-phosphate. Preincubation of the effector cells, obtained from fresh whole blood, with mannose-6-phosphate, fructose-1-phosphate, or fructose-6-phosphate did not inhibit cytotoxicity, which indicated that these hexose phosphates are not nonspecifically toxic towards the effector lymphocytes. Mannose-6-phosphate and the stereochemically similar fructose-1-phosphate are more potent inhibitors than fructose-6-phosphate in terms of concentration required and time of onset of effect. Inhibition of cytotoxicity by mannose-6-phosphate varied with target cell type: F-265 is protected at much lower concentrations of mannose-6-phosphate ( |
| doi_str_mv | 10.1073/pnas.78.9.5797 |
| format | Article |
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This inhibition is not observed with mannose, glucose, fucose, glucose 6-phosphate, mannose 1-phosphate, galactose 1-phosphate, or galactose 6-phosphate. Preincubation of the effector cells, obtained from fresh whole blood, with mannose-6-phosphate, fructose-1-phosphate, or fructose-6-phosphate did not inhibit cytotoxicity, which indicated that these hexose phosphates are not nonspecifically toxic towards the effector lymphocytes. Mannose-6-phosphate and the stereochemically similar fructose-1-phosphate are more potent inhibitors than fructose-6-phosphate in terms of concentration required and time of onset of effect. Inhibition of cytotoxicity by mannose-6-phosphate varied with target cell type: F-265 is protected at much lower concentrations of mannose-6-phosphate (<1 mM) than is either Molt-4 or K-562. The inhibition of NCMC is also observed with the inhibitors of lysosomal function, NH4Cl, and chloroquine. The presence of a functional mannose-6-phosphate receptor on target cells was demonstrated: (i) Gelonin, a seed protein that inactivates the eukaryotic ribosome but is nontoxic to intact cells, was covalently linked to monophosphopentamannose, and this conjugate was toxic to both K-562 and F-265 target cells, the latter being by far the more sensitive; and (ii) chloroquine, NH4Cl, and mannose-6-phosphate all inhibited the toxicity of gelonin-monophosphopentamannose. These results suggest either that a cytolytic lymphokine contains a hexose phosphate residue and may be taken up by target cells through the lysosomal/mannose 6-phosphate pathway or that such a residue is involved in target cell--effector cell recognition.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.78.9.5797</identifier><identifier>PMID: 6946516</identifier><language>eng</language><publisher>United States: National Academy of Sciences of the United States of America</publisher><subject>Cell lines ; Cytotoxicity ; Cytotoxicity, Immunologic - drug effects ; Fructosephosphates - pharmacology ; Hexosephosphates - pharmacology ; Hexoses ; Hexoses - pharmacology ; Humans ; Immunity, Innate - drug effects ; Lymphocytes ; Lymphokines - physiology ; Lysosomes - physiology ; Mannosephosphates - pharmacology ; Molecules ; Natural killer cells ; Phosphates ; Receptors ; Receptors, Drug - physiology ; Sugars ; Toxicity</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 1981-09, Vol.78 (9), p.5797-5801</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4027-cf3079e9897db5bd0b02f28870239afa8fe1e972db5f9e1d9487d666889664c63</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/78/9.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/11555$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/11555$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/6946516$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Forbes, James T.</creatorcontrib><creatorcontrib>Bretthauer, Roger K.</creatorcontrib><creatorcontrib>Oeltmann, Thomas N.</creatorcontrib><title>Mannose 6-, Fructose 1-, and Fructose 6-Phosphates Inhibit Human Natural Cell-Mediated Cytotoxicity</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>In vitro human natural cell-mediated cytotoxicity (NCMC) to K-562, Molt-4, and F-265 cells is inhibited in a dose-dependent manner by mannose 6-phosphate, fructose 1-phosphate, and fructose 6-phosphate. This inhibition is not observed with mannose, glucose, fucose, glucose 6-phosphate, mannose 1-phosphate, galactose 1-phosphate, or galactose 6-phosphate. Preincubation of the effector cells, obtained from fresh whole blood, with mannose-6-phosphate, fructose-1-phosphate, or fructose-6-phosphate did not inhibit cytotoxicity, which indicated that these hexose phosphates are not nonspecifically toxic towards the effector lymphocytes. Mannose-6-phosphate and the stereochemically similar fructose-1-phosphate are more potent inhibitors than fructose-6-phosphate in terms of concentration required and time of onset of effect. Inhibition of cytotoxicity by mannose-6-phosphate varied with target cell type: F-265 is protected at much lower concentrations of mannose-6-phosphate (<1 mM) than is either Molt-4 or K-562. The inhibition of NCMC is also observed with the inhibitors of lysosomal function, NH4Cl, and chloroquine. The presence of a functional mannose-6-phosphate receptor on target cells was demonstrated: (i) Gelonin, a seed protein that inactivates the eukaryotic ribosome but is nontoxic to intact cells, was covalently linked to monophosphopentamannose, and this conjugate was toxic to both K-562 and F-265 target cells, the latter being by far the more sensitive; and (ii) chloroquine, NH4Cl, and mannose-6-phosphate all inhibited the toxicity of gelonin-monophosphopentamannose. These results suggest either that a cytolytic lymphokine contains a hexose phosphate residue and may be taken up by target cells through the lysosomal/mannose 6-phosphate pathway or that such a residue is involved in target cell--effector cell recognition.</description><subject>Cell lines</subject><subject>Cytotoxicity</subject><subject>Cytotoxicity, Immunologic - drug effects</subject><subject>Fructosephosphates - pharmacology</subject><subject>Hexosephosphates - pharmacology</subject><subject>Hexoses</subject><subject>Hexoses - pharmacology</subject><subject>Humans</subject><subject>Immunity, Innate - drug effects</subject><subject>Lymphocytes</subject><subject>Lymphokines - physiology</subject><subject>Lysosomes - physiology</subject><subject>Mannosephosphates - pharmacology</subject><subject>Molecules</subject><subject>Natural killer cells</subject><subject>Phosphates</subject><subject>Receptors</subject><subject>Receptors, Drug - physiology</subject><subject>Sugars</subject><subject>Toxicity</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1981</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptUT1PwzAQtRAIysfKgISUiYkEO3H8MTCgilIkCgwwW47jUFepXWIHtf-eRC2lSEynu_fe3Ts9AM4RTBCk2c3CSp9QlvAkp5zugQGCHMUEc7gPBhCmNGY4xUfg2PsZhJDnDB6CQ8IxyREZADWR1jqvIxJfR6OmVaFvUNdIW_4OSPw6dX4xlUH76NFOTWFCNG7n0kbPMrSNrKOhrut4okvTccpouAouuKVRJqxOwUEla6_PNvUEvI_u34bj-Onl4XF49xQr3PtUVQYp15xxWhZ5UcICplXKGIVpxmUlWaWR5jTtwIprVHLMaEkIYYwTghXJTsDteu-iLea6VNqGzphYNGYum5Vw0oi_iDVT8eG-RIYZI73-aqNv3GerfRBz41X3lrTatV6gHJOU4LQjJmuiapz3ja62NxAUfSqiT0VQJrjoU-kEl7vOtvRNDDuXe90PutWLqq3roJdhZ9G_xA6_WOMzH1zzawvleZ59AzeUqa8</recordid><startdate>19810901</startdate><enddate>19810901</enddate><creator>Forbes, James T.</creator><creator>Bretthauer, Roger K.</creator><creator>Oeltmann, Thomas N.</creator><general>National Academy of Sciences of the United States of America</general><general>National Acad Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>19810901</creationdate><title>Mannose 6-, Fructose 1-, and Fructose 6-Phosphates Inhibit Human Natural Cell-Mediated Cytotoxicity</title><author>Forbes, James T. ; Bretthauer, Roger K. ; Oeltmann, Thomas N.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4027-cf3079e9897db5bd0b02f28870239afa8fe1e972db5f9e1d9487d666889664c63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1981</creationdate><topic>Cell lines</topic><topic>Cytotoxicity</topic><topic>Cytotoxicity, Immunologic - drug effects</topic><topic>Fructosephosphates - pharmacology</topic><topic>Hexosephosphates - pharmacology</topic><topic>Hexoses</topic><topic>Hexoses - pharmacology</topic><topic>Humans</topic><topic>Immunity, Innate - drug effects</topic><topic>Lymphocytes</topic><topic>Lymphokines - physiology</topic><topic>Lysosomes - physiology</topic><topic>Mannosephosphates - pharmacology</topic><topic>Molecules</topic><topic>Natural killer cells</topic><topic>Phosphates</topic><topic>Receptors</topic><topic>Receptors, Drug - physiology</topic><topic>Sugars</topic><topic>Toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Forbes, James T.</creatorcontrib><creatorcontrib>Bretthauer, Roger K.</creatorcontrib><creatorcontrib>Oeltmann, Thomas N.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Forbes, James T.</au><au>Bretthauer, Roger K.</au><au>Oeltmann, Thomas N.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mannose 6-, Fructose 1-, and Fructose 6-Phosphates Inhibit Human Natural Cell-Mediated Cytotoxicity</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>1981-09-01</date><risdate>1981</risdate><volume>78</volume><issue>9</issue><spage>5797</spage><epage>5801</epage><pages>5797-5801</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>In vitro human natural cell-mediated cytotoxicity (NCMC) to K-562, Molt-4, and F-265 cells is inhibited in a dose-dependent manner by mannose 6-phosphate, fructose 1-phosphate, and fructose 6-phosphate. This inhibition is not observed with mannose, glucose, fucose, glucose 6-phosphate, mannose 1-phosphate, galactose 1-phosphate, or galactose 6-phosphate. Preincubation of the effector cells, obtained from fresh whole blood, with mannose-6-phosphate, fructose-1-phosphate, or fructose-6-phosphate did not inhibit cytotoxicity, which indicated that these hexose phosphates are not nonspecifically toxic towards the effector lymphocytes. Mannose-6-phosphate and the stereochemically similar fructose-1-phosphate are more potent inhibitors than fructose-6-phosphate in terms of concentration required and time of onset of effect. Inhibition of cytotoxicity by mannose-6-phosphate varied with target cell type: F-265 is protected at much lower concentrations of mannose-6-phosphate (<1 mM) than is either Molt-4 or K-562. The inhibition of NCMC is also observed with the inhibitors of lysosomal function, NH4Cl, and chloroquine. The presence of a functional mannose-6-phosphate receptor on target cells was demonstrated: (i) Gelonin, a seed protein that inactivates the eukaryotic ribosome but is nontoxic to intact cells, was covalently linked to monophosphopentamannose, and this conjugate was toxic to both K-562 and F-265 target cells, the latter being by far the more sensitive; and (ii) chloroquine, NH4Cl, and mannose-6-phosphate all inhibited the toxicity of gelonin-monophosphopentamannose. These results suggest either that a cytolytic lymphokine contains a hexose phosphate residue and may be taken up by target cells through the lysosomal/mannose 6-phosphate pathway or that such a residue is involved in target cell--effector cell recognition.</abstract><cop>United States</cop><pub>National Academy of Sciences of the United States of America</pub><pmid>6946516</pmid><doi>10.1073/pnas.78.9.5797</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Cell lines Cytotoxicity Cytotoxicity, Immunologic - drug effects Fructosephosphates - pharmacology Hexosephosphates - pharmacology Hexoses Hexoses - pharmacology Humans Immunity, Innate - drug effects Lymphocytes Lymphokines - physiology Lysosomes - physiology Mannosephosphates - pharmacology Molecules Natural killer cells Phosphates Receptors Receptors, Drug - physiology Sugars Toxicity |
| title | Mannose 6-, Fructose 1-, and Fructose 6-Phosphates Inhibit Human Natural Cell-Mediated Cytotoxicity |
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