CN1036794A - A kind of method that increases yield of cytokins - Google Patents
A kind of method that increases yield of cytokins Download PDFInfo
- Publication number
- CN1036794A CN1036794A CN89102021.7A CN89102021A CN1036794A CN 1036794 A CN1036794 A CN 1036794A CN 89102021 A CN89102021 A CN 89102021A CN 1036794 A CN1036794 A CN 1036794A
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- China
- Prior art keywords
- cytokinin
- value
- cell
- temperature
- insulation
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- Pending
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- 238000000034 method Methods 0.000 title claims abstract description 21
- UQHKFADEQIVWID-UHFFFAOYSA-N cytokinin Natural products C1=NC=2C(NCC=C(CO)C)=NC=NC=2N1C1CC(O)C(CO)O1 UQHKFADEQIVWID-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000004062 cytokinin Substances 0.000 claims abstract description 19
- 238000004519 manufacturing process Methods 0.000 claims abstract description 8
- 238000009413 insulation Methods 0.000 claims description 9
- 230000001939 inductive effect Effects 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 2
- 210000004027 cell Anatomy 0.000 description 14
- 102000000412 Annexin Human genes 0.000 description 6
- 108050008874 Annexin Proteins 0.000 description 6
- 102000000588 Interleukin-2 Human genes 0.000 description 6
- 108010002350 Interleukin-2 Proteins 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 108010050904 Interferons Proteins 0.000 description 4
- 102000014150 Interferons Human genes 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 229940079322 interferon Drugs 0.000 description 4
- 235000015097 nutrients Nutrition 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 238000013016 damping Methods 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 210000000265 leukocyte Anatomy 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 230000000050 nutritive effect Effects 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 206010018910 Haemolysis Diseases 0.000 description 2
- 241000711408 Murine respirovirus Species 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 235000010418 carrageenan Nutrition 0.000 description 2
- 229920001525 carrageenan Polymers 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 108010074605 gamma-Globulins Proteins 0.000 description 2
- 230000008588 hemolysis Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000002555 ionophore Substances 0.000 description 2
- 230000000236 ionophoric effect Effects 0.000 description 2
- PHEDXBVPIONUQT-RGYGYFBISA-N phorbol 13-acetate 12-myristate Chemical compound C([C@]1(O)C(=O)C(C)=C[C@H]1[C@@]1(O)[C@H](C)[C@H]2OC(=O)CCCCCCCCCCCCC)C(CO)=C[C@H]1[C@H]1[C@]2(OC(C)=O)C1(C)C PHEDXBVPIONUQT-RGYGYFBISA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- TUNFSRHWOTWDNC-UHFFFAOYSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 2
- QGVLYPPODPLXMB-UBTYZVCOSA-N (1aR,1bS,4aR,7aS,7bS,8R,9R,9aS)-4a,7b,9,9a-tetrahydroxy-3-(hydroxymethyl)-1,1,6,8-tetramethyl-1,1a,1b,4,4a,7a,7b,8,9,9a-decahydro-5H-cyclopropa[3,4]benzo[1,2-e]azulen-5-one Chemical compound C1=C(CO)C[C@]2(O)C(=O)C(C)=C[C@H]2[C@@]2(O)[C@H](C)[C@@H](O)[C@@]3(O)C(C)(C)[C@H]3[C@@H]21 QGVLYPPODPLXMB-UBTYZVCOSA-N 0.000 description 1
- HBOMLICNUCNMMY-KJFJCRTCSA-N 1-[(4s,5s)-4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1C1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-KJFJCRTCSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 108010062580 Concanavalin A Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000959820 Homo sapiens Interferon alpha-1/13 Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- FAIXYKHYOGVFKA-UHFFFAOYSA-N Kinetin Natural products N=1C=NC=2N=CNC=2C=1N(C)C1=CC=CO1 FAIXYKHYOGVFKA-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 102000018594 Tumour necrosis factor Human genes 0.000 description 1
- 108050007852 Tumour necrosis factor Proteins 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 229940088623 biologically active substance Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- QANMHLXAZMSUEX-UHFFFAOYSA-N kinetin Chemical compound N=1C=NC=2N=CNC=2C=1NCC1=CC=CO1 QANMHLXAZMSUEX-UHFFFAOYSA-N 0.000 description 1
- 229960001669 kinetin Drugs 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- QGVLYPPODPLXMB-QXYKVGAMSA-N phorbol Natural products C[C@@H]1[C@@H](O)[C@]2(O)[C@H]([C@H]3C=C(CO)C[C@@]4(O)[C@H](C=C(C)C4=O)[C@@]13O)C2(C)C QGVLYPPODPLXMB-QXYKVGAMSA-N 0.000 description 1
- 239000002644 phorbol ester Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4721—Lipocortins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/555—Interferons [IFN]
- C07K14/56—IFN-alpha
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/555—Interferons [IFN]
- C07K14/57—IFN-gamma
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Gastroenterology & Hepatology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Zoology (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Toxicology (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
The present invention relates to the method that a kind of amount with increase prepares cytokinin, wherein under different temperature and/or pH value condition, finish and induce and production process.
Description
The present invention relates to prepare with the productive rate that has improved the method for cytokinin, wherein to induce with producing be to finish under different temperature and pH value condition.
Cytokinin between living organism tissue and cell function connect each other and adjusting aspect play an important role." cytokinin " (" Cytokin ") comprises that producing justacrine by viable cell learns active molecule or molecule group to all the tool lives in its surrounding environment.For example, comprising interleukin-, Interferon, rabbit (IFNs), lipocortin (lipocartin), tumour necrosis factor etc.
Under suitably inducible factor participated in, viable cell can also produce cytokinin in vitro.Above-mentioned inducible factor can be virus, phytohaemagglutinin, mitogen, phorbol ester, ionophore, synthetic Yeast Nucleic Acid etc.As seen, can pass through the natural biologically active substance of proper method suitability for industrialized production.
Also can promptly use genetic manipulation to prepare cytokinin, wherein the humans and animals cell be placed nutrient solution to make it under the effect of inductor, to produce cytokinin, and then from substratum, reclaim cytokinin by so-called natural method.Relevant preparation method is record to some extent in the literature: prepare lipocortin (referring to B.Rothhut etc., FEBS Lett.219,169(1987)) as using the glucocorticoid inducible agent; Use the PMA inductor to prepare B-cell stimulating factor (IL-4) (referring to J.HuLi etc., J.EXP.Med., 165,157(1987)); Use the concanavalin A inductor to prepare interleukin II (referring to K.Kato etc., Biochem.Biophys.Res.Commun.127,182(1985)); And use the Sendai virus inductor to prepare methods such as interferon-alpha (referring to K.Cantell etc., Methods Enzymol.72,29(1981)).
The common feature of aforesaid method is that induce and the production process of cytokinin carry out under identical conditions.
Invention is based on such understanding: promptly under only inductive condition, also can occur producing the inhibition factor earlier, and this factor can be avoided by suitable adjustment envrionment conditions.
Use method of the present invention, can under conditions in vitro, increase the productive rate of the cytokinin of various cell generations significantly.
Usually can be by handling corresponding cell with one or more inductors, and then the insulation certain hour prepares cytokinin.Available currently known methods is received the cell agonist that is secreted in the nutritive medium back and forth.
The objective of the invention is by reducing the effect of cell kinetin synthesis inhibitoroy factor, thereby improve the output of cytokinin.
The method according to this invention can change heat-retaining condition at interval by reasonable time, stoping the influence of supressor, thereby improves the output of cytokinin greatly.
We find that after exponential phase, delaying cytokinin synthetic biological process can more strengthen at the cytokinin synthetic.Since exponential phase, it is less that cytokinin produces the susceptibility that heat-retaining condition is changed, and also more less than the suffered restraining effect of the above-mentioned building-up process that slows down.Therefore, can and select the suitable time to prolong the production interval by the appropriate change heat-retaining condition.
The following example will be illustrated the present invention in more detail.
Do not mentioning the place of regulating the pH value, the pH value is a physiological value, promptly 7.2～7.4.
Embodiment 1
Increase human leukocyte interferon-'s productive rate by the pH value that changes insulation.
Remove the red corpuscle that pollutes with 0.83% ammonium chloride solution through haemolysis several times, obtain the buffy coat (Buffy coat, the isolating white corpuscle component that is rich in from fresh human blood) of purifying, then with the white corpuscle of gained with 1 * 10
7The concentration of individual cell/ml is suspended in and contains inorganic salt, glucose and 1mg/ml and do not have in the proper nutrition liquid of gamma Globulin human serum.In above-mentioned suspension, add the 200IU/ml human leukocyte interferon-, mixing solutions is incubated 2 hours down in 37 ℃.And then in cell suspending liquid, add the Sendai virus of 100HA unit/ml, and with mixing solutions in 37 ℃ of insulations 2 hours down.
After 2 hours, in the bottle that contains cell suspending liquid, add a certain amount of Tris-HCl damping fluid, with its P
HValue is transferred to 7, is incubated 20 hours then.In nutrient solution, isolate white corpuscle through centrifugal.The disease-resistant inflexible Ъ of the Interferon, rabbit crude product that so makes scoops up 00 with a dustpan, and 000IU/ml that is to say than not transferring P with damping fluid
HBe worth the prepared interferon anti-reflecting virus high twice of tiring.
Embodiment 2
Change holding temperature and P
HValue is to increase the productive rate of human leukocyte IFN-and interleukin II.
Can in same cell culture, prepare IFN-and interleukin II simultaneously.
White corpuscle that is made by fresh buffy coat or exhausted white corpuscle when formerly preparing Interferon, rabbit all can be used for this production process.Can be by the cell suspension of the preparation of the method described in the embodiment 1.
With white corpuscle with 1 * 10
7～2 * 10
7The dope of cell/ml is suspended in and contains 1mg/ml and do not have in the known nutrient solution of gamma Globulin human serum.Can add down 10～20 μ g/ml concanavalin As or 1～10 μ g/ml phytohaemagglutinin or 20～10 μ g/ml mesereine in 37 ℃, or 0.5～2 μ g A 23187 ionophores or 5～30ng/ml phorbol tetradecanoic acid acetic ester are induced.Add inductor after 3 hours, will contain leukocytic bottle and place 30 ℃ of thermostat containers, P
HBe transferred to 7 these mixing solutionss of back insulation.After the insulation, centrifugal from the nutritive medium that contains IFN-and interleukin II (IL-2), to isolate cell.
Antiviral the tiring of IFN-is 15,000IU/ml, and antiviral the tiring of interleukin II is 1,300IU/ml.These potency ratios are not transferred P with damping fluid under 37 ℃ of steady temperatures
HTiring of the product that makes is high 2～2.5 times.
Embodiment 3
Change holding temperature to increase the productive rate of lipocortin
With the red corpuscle of 0.83% ammonium chloride solution, by the buffy coat that makes purifying in the fresh human blood through the pollution of haemolysis removal several times.Then with the pure white cell of gained with 1 * 10
7The concentration of individual cell/ml is suspended in the nutrient solution that does not contain serum, is incubated 2 hours down with the processing of 1 μ M dexamethasone and in 37 ℃.Again holding temperature is transferred to 30～32 ℃ and is continued insulation 15 to 20 hours.Then from nutritive medium, remove leucocyte-removing with centrifuging.The gained supernatant liquor is the raw product of lipocortin, and the inflammation that its on Carrageenan is brought out has very strong anti-inflammatory action.The lipocortin crude product that makes under non-constant temperature is higher 2～2.5 times than the anti-inflammatory action of the lipocortin that makes under steady temperature.The size of anti-inflammatory action is by the intravital carrageenin test determination of mouse by the described method of people such as Winter (Pract.Soc.Exp.Biol.Med., 111,644(1962)).
Claims (5)
1, a kind ofly prepare the method for cytokinin with higher yields, it is included in to finish under different temperature and/or the pH value condition and induces and production process.
2, according to the method for claim 1, it is included between inductive phase than having used lower pH and/or holding temperature at production period.
3, according to the method for claim 1 or 2, it comprises is transferred to the pH value of insulation 7 and/or holding temperature is transferred to 15～40 ℃ in process of production, and better 20～35 ℃, best 25～32 ℃.
4, according to each method in the claim 1 to 3, it is included in pH value and/or temperature that the synthetic beginning of cytokinin back changes insulation.
5, according to each method in the claim 1 to 4, it is included in the cytokinin synthetic changes insulation in exponential phase pH value and/or temperature.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU881049A HU202594B (en) | 1988-03-04 | 1988-03-04 | Process for increasing yield of leucoquines |
| HU1049/88 | 1988-03-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1036794A true CN1036794A (en) | 1989-11-01 |
Family
ID=10952631
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN89102021.7A Pending CN1036794A (en) | 1988-03-04 | 1989-03-03 | A kind of method that increases yield of cytokins |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JPH0724595B2 (en) |
| CN (1) | CN1036794A (en) |
| AT (1) | AT392800B (en) |
| DE (1) | DE3907114A1 (en) |
| HU (1) | HU202594B (en) |
| IT (1) | IT1229193B (en) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2906160A1 (en) * | 1979-02-17 | 1980-09-04 | Thomae Gmbh Dr K | Interferon prodn. - using stimulators to increase yields |
| US4357422A (en) * | 1980-08-14 | 1982-11-02 | Massachusetts Institute Of Technology | Method of enhancing interferon production |
| JPS57105195A (en) * | 1980-10-24 | 1982-06-30 | Nat Res Dev | Production of interferon |
| JPS6296083A (en) * | 1985-10-21 | 1987-05-02 | Toray Ind Inc | Culture of antimal cell |
-
1988
- 1988-03-04 HU HU881049A patent/HU202594B/en not_active IP Right Cessation
-
1989
- 1989-03-03 IT IT8919632A patent/IT1229193B/en active
- 1989-03-03 JP JP1050209A patent/JPH0724595B2/en not_active Expired - Lifetime
- 1989-03-03 AT AT481/89A patent/AT392800B/en not_active IP Right Cessation
- 1989-03-03 CN CN89102021.7A patent/CN1036794A/en active Pending
- 1989-03-06 DE DE3907114A patent/DE3907114A1/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| IT1229193B (en) | 1991-07-25 |
| ATA48189A (en) | 1990-11-15 |
| IT8919632A0 (en) | 1989-03-03 |
| HUT50218A (en) | 1989-12-28 |
| JPH01281095A (en) | 1989-11-13 |
| AT392800B (en) | 1991-06-10 |
| JPH0724595B2 (en) | 1995-03-22 |
| DE3907114C2 (en) | 1991-12-19 |
| HU202594B (en) | 1991-03-28 |
| DE3907114A1 (en) | 1989-09-14 |
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