Source: https://patents.google.com/patent/US4603106?oq=6101531
Timestamp: 2018-03-22 01:07:24
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Matched Legal Cases: ['§120', 'art 1982', 'art 1985', 'art 1987', 'art 1', 'art 1', 'art 1', 'art 1', 'art 1', 'art 2', 'art 2', 'art 1']

US4603106A - Lipoprotein lipase suppression by endotoxin-induced mediator (shock assay) - Google Patents
Lipoprotein lipase suppression by endotoxin-induced mediator (shock assay) Download PDF
US4603106A
US4603106A US06414098 US41409882A US4603106A US 4603106 A US4603106 A US 4603106A US 06414098 US06414098 US 06414098 US 41409882 A US41409882 A US 41409882A US 4603106 A US4603106 A US 4603106A
US06414098
ROCKERFELLER UNIVERSITY A CORP OF NY
The instant application is a continuation-in-part of Ser. No. 351,290, filed Feb. 22, 1982 now abandoned, by the same applicants, which in turn is a continuation-in-part of Ser. No. 299,932 filed Sept. 8, 1981 now abandoned. Applicants claim the benefit of these applications under 35 U.S.C. §120.
FIG. 1A shows the effect of serum from endotoxinsensitive mice treated with endotoxin on adipose tissue LPL activity in endotoxin-sensitive mice. Mediator activity was observed and conclusions drawn as set forth in Example I, paragraph E herein. The data are expressed as the mean (±SEM) of six animals for each group.
FIG. 1B shows the effect of serum from endotoxin-sensitive mice treated with endotoxin on adipose tissue LPL activity in endotoxin-resistant mice. The data are expressed as the mean (± SEM) of three animals for each group.
FIG. 2 shows the effect of medium from exudate cell cultures on adipose tissue LPL in endotoxin-resistant mice. The data are presented as the mean (± SEM) of four or five animals.
FIG. 3 shows the effect of conditioned medium from endotoxin-treated mouse peritoneal exudate cells over lipoprotein lipase activity of 3T3-L1 cells. Data are expressed as mean ± SEM (n=4).
FIG. 4 shows the effect of conditioned medium from endotoxin-treated mouse peritoneal exudate cells on the activities of acetyl CoA carboxylase and fatty acid synthetase in 3T3-L1 cells. Three hundred (300) μl of conditioned medium was added to cultures of 3T3-L1 cells (4.2×106 cells/dish) in 6 cm dishes containing 3.5 ml of DME medium and 10% fetal calf serum. After the indicated times of incubation, the enzymatic activity of acetyl CoA carboxylase (identified by the symbol " ○") and fatty acid synthetase (identified by the symbol " ") on a digitonin releaseable cytosolic fraction of the cells was assessed.
FIG. 5 shows the effect of mediator that suppresses the synthesis of acetyl CoA carboxylase. At the indicated times after exposure of the 3T3-L1 cells to the mediator (300 μl of conditioned medium), the cells were pulse-labeled with 0.5 mCi of 35 S-methionine for 1 hour. Cytosolic fractions were obtained by digitonin treatment of a monolayer. Aliquots of the cytosolic fractions (2×105 cpm for all determinations) were incubated with anti-acetyl CoA carboxylase and the immunoprecipitable material isolated and characterized as described in Example II; infa. Panel A: Autoradiogram of a 7.5%-acrylamide-0.1% SDS gel analysis of immunoadsorbable protein. Lane 1--control, without exposure to mediator; Lanes 2, 3, and 4--exposure of the cells to the mediator for 3, 6 and 20 hours, respectively. Panel B: Results of a densitometric scan of the autoradiogram, indicating percent of immunoadsorbable material remaining relative to control, after exposure to the mediator.
FIG. 8 shows the effect of mediator on protein synthesis in the cytosolic fraction of the cells. Autoradiogram of a 7.5%-acrylamide-0.1% SDS gel analysis of 35 S-methionine labeled cytosolic protein after exposure of the cells to the mediator. 3T3-L1 cells were pulse labeled and the soluble protein was obtained by digitonin as described in Example II. Aliquots (2×105 cpm) of the cytosolic fraction for each time point were applied to the gel and electrophoresed. Lanes 1 and 2, control without exposure to mediator; Lanes 3 and 4, 1 hour exposure to the mediator; Lanes 5 and 6, 3 hours of exposure; Lanes 7 and 8, 6 hours of exposure; Lanes 9 and 10, 20 hours of exposure to conditioned medium from mouse peritoneal exudate cells not exposed to endotoxin; Lanes 11 and 12, exposure of cells to mediator for 20 hours.
Friend cells (clone DS-19) were incubated for 96 hours in the absence or in the presence of Me2 SO (1.5 vol %). Conditioned media (80 μl/ml of growth medium) from mouse peritoneal macrophage cultures stimulated or not stimulated with endotoxin (5 μg/ml) were added at the beginning of culture. Cell members were counted with a Cytograf model 6300 and expressed as per cent inhibition of the control cells. Cell number in untreated control culture was 3×106 cells/ml. Heme content was determined fluorometrically as described previously (Sassa, S., Granick, S., Chang, C. and Kappas, A. (1975) In Erythropoiesis, ed. by K.Nakao, J. W. Fisher and F. Takaku (University of Tokyo Press, Tokyo) pp. 383-396) Data are the mean of duplicate determinations. The number of trypan blue positive cells assessed by Cytograf counting was 8-10% for all cultures.
______________________________________Cell number    3.0 (× 10.sup.-6 /ml)ALA dehydratase          3.00 (nmol PBG/10.sup.6 cells, h)PBG deaminase  120 (pmol uroporphyrinogen/10.sup.6          cells, h)Protoporphyrin 0.57 (pmol/10.sup.6 cells)Heme           520 (pmol/10.sup.6 cells)______________________________________
Med*+Ab.sub.1 =Med*Ab.sub.1                                A.
Med+Ab.sub.1 *=MedAb.sub.1                                 B.
Med+Ab.sub.1 +Ab*.sub.2 =Med Ab.sub.1 Ab.sub.2 *           C.
TABLE______________________________________                Mediator  MediatorEntity               Production                          Effect______________________________________Dexamethasone 10.sup.-6 M                +         -Aspirin 10.sup.-3 M  -         -Indomethacin 10.sup.-5 M                -         -Nalaxone 10.sup.-5 M -         -Thyroid Releasing Factor 10.sup.-7 M                -         -(+ denotes yes; - denotes no)______________________________________
EXAMPLE I Isolation of Mediator Activity Compositions
B. Assay for Serum Triglyceride Concentration and Tissue Lipoprotein Lipase Activity: The triglyceride concentration was measured with an enzymatic assay (Triglyceride Test Set No. 961, Hycel Inc., Houston, Tex.). Lipoprotein lipase activity was assayed by the methods of Pykalisto, et al., PROC. SOC. EXP. BIOL. MED., 148 at 297 (1975); and Taskinen, et al., DIABETOLOGIA 17 at 351 (1979), both incorporated herein, with some modifications. Epididymal fat pads were excised immediately after the decapitation of each mouse. The tissues were rinsed in sterile Dulbecco's Modified Eagle medium (DME) (Gibco, Grand Island, N.Y.) containing 2% bovine serum albumin (fraction V, Reheis Chemical Company, Phoenix, Ariz.) and blotted on sterile filter paper. The tissues were minced with scissors, put into pre-weighed sterile polypropylene culture tubes (17×100 mm, Falcon Division of Becton, Dickinson and Company, Cockeysville, Md.) containing 1 ml of DME medium supplemented with 2% bovine serum albumin, and 2 U of heparin to release LPL (Lipo-Hepin, Riker Laboratories, Inc., Northridge, Calif.). Tubes with the tissues were sealed under 5% CO2, balance air and incubated at room temperature with continuous gentle shaking. Tissue weight was determined by the difference of the weights of the tube before and after the addition of the tissue. Approximately 100-300 mg of tissue was removed and the activity of lipoprotein lipase released from the tissue was determined.
The enzyme assay was carried out by the method of Nilsson-Ehle and Shotz, J. LIPID. RES. 17 at 536 (1976), incorporated herein, with minor modifications. The samples were incubated at 37° C. for 90 minutes of incubation. Each sample was assayed in duplicate. One milliunit of the enzyme activity was defined as one nanomole of free fatty acid released per minute. The enzyme activity released per gram of wet tissue was compared between experimental groups and control groups of each study since there was considerable variation of LPL activity day to day. In order to compare the data between experiments, the data was expressed as percent of the average activity of the control group. The range observed in C3H/HeN mice was from 32 to 59 mU/g for adipose tissue. Values to 31 of 172 mU/g for adipose tissue were observed in C3H/HeJ mice.
C. Collection of Serum for Endotoxin Treated Mice: Blood was obtained under sterile conditions from the axillary pit of C3H/HeN mice 2 hours after i.p. injection of endotoxin (either 2 or 100 μg/mouse) in 0.1 ml of saline or saline alone. Serum was prepared within one hour after bleeding and either used immediately or kept at -80° C. until use.
G. Isolation of Mediator Activity Compositions from Mouse Peritoneal Exudate Cells: Culture medium is collected from mouse peritoneal exudate cells cultured in RPMI-1640 growth medium exposed to 10 μg/ml of endotoxin for 24 to 36 hours and centrifuged at 500 rpm for 10 minutes at 4° C. The supernatant is subjected to ultrafiltration through an Amicon PM-10 membrane with a 10,000-Dalton cut-off. The volume of the retentate is concentrated by filtration to approximately 7 ml, placed on a Sephacryl 300 column (1.695 cm) and eluted with phosphate-buffered saline (PBS) (pH 7.4) at 4 ml/hr and 4° C. The volume of each collected fraction was 3.6 ml. The fractions were analyzed for LPL activity. Fractions eluting at 108 to 115 ml and 133 to 140 ml were found to be active in the LPL assay. The molecular weights of the mediator active compositions in these fractions are about 300,000 and 70,000 Daltons, respectively.
Lipoprotein lipase assays were performed within 30 minutes after the preparation of each sample in duplicate by the method of Nilsson-Ehle and Shotz [J. LIPID. RES. 17 at 536-541 (1976)] with minor modifications. Briefly, 75 μl of enzyme was mixed with 25 μl of substrate containing 22.7 mM[3H]-triolein (1.4 uCi per mole), 2.5 mg per ml of lecithin, 40 mg per ml bovine serum albumin, 33% (V/V) human serum and 33% (V/V) glycerol in 0.27 M Tris-HC1, pH 8.1, and incubated at 37° C. for 90 minutes. One milliunit of enzyme activity was defined as the release of one nanomole of fatty acid per minute. The lipase activity in all three compartments was inhibited >90% by addition of 1 M NaCl and >80% by omission of serum which is the source of apolipoprotein C-II needed for enzymatic activity.
The cells (4×105 cells per cm2d) were incubated in serum-free RPMI-1640 medium for 3 hours after which nonadherent cells were removed by washing 3 times with medium. Cells adhering to the dish were primarily macrophages. These cells were further incubated in serum-free RPMI-1640 medium in the presence or absence of 10 μg per ml of endotoxin. After 24 hours, the culture medium was removed and centrifuged at 1,000×g for 5 minutes at 4° C. The supernatant of conditioned medium obtained from cells exposed to endotoxin was assayed and found to contain the mediator substance that lowers LPL in 3T3-L1 cells.
E. Labeling of Cellular Proteins: A 6-cm plate containing induced 3T3-L1 cells was washed twice with 5 ml of methionine-free medium and incubated for 1 hour with 2 ml of the same medium containing 0.5 mCi of L-[35 S]-methionine during which period the rate of [35 S]-methionine incorporation into cellular protein was linear. The medium was removed, the cell monolayer washed twice with phosphate-buffered saline, ph 7.4, and the soluble cytosolic proteins released by the digitonin method of Mackall, et al, supra. The remainder of the cell monolayer containing the membranous fraction was then scraped into 2.0 ml of 100 mM HEPES buffer, pH 7.5, containing 0.5% of the nonionic detergent NP-40 and 1 mM phenylmethylsulfonylfluoride. After trituration in a Pasteur pipet, the suspension was centrifuged at 10,000×g for 10 minutes at 4° C., and the supernatant saved.
[35 S]-methionine incorporation into acid insoluble material was determined by adding 20 μl of digitonin or NP-40 released material to 0.5 ml of ice cold 20% TCA with 25 μl of 0.5% bovine serum albumin added as carrier. After sitting at 4° C. for 1 hour, the mixture was centrifuged at 2,000×g for 5 minutes. The pellet was incubated in 0.5 ml of 1 M NH4 OH at 37° C. for 30 minutes. The protein was reprecipitated on addition of 5.0 ml of ice cold 10% TCA and filtered on Whatman GF/C filters. The filters were extracted with diethyl ether and the amount of radiolabel determined.
After 2 hours at 25° C., 100 μl of 10% IgG-SORB were added and the labeled enzymes isolated from the mixture by the method of Student, et al., supra. Polyacrylamide-SDS gels were run according to the method of Laemmli, and prepared for fluorography by use of En3 Hance according to the manufacturer's instructions.
D. Induction of Erythroid Differentiation: Two types of incubation protocols were used to assess erythroid differentiation of Friend cells. In certain experiments illustrated in FIGS. 10-13, the cells (5×104 cells/ml) were incubated at 37° C., in 5% CO2 in humidified air for 18 hours. The inducing chemicals, e.g. Me2 SO, HMBA, butyric acid, hypoxanthine or hemin were added with or without macrophage mediator(s) and cultures were incubated for 96 hours without changing the growth medium. In other experiments such as those with results illustrated in FIG. 14, the cells (105 cells/ml) were incubated for 18 hours, then Me2 SO and the macrophage mediator were added as above. The cultures were maintained at 2×105 cells/ml by diluting the cell suspension daily with fresh medium containing the chemical inducer with or without the macrophage mediator. This procedure required more macrophage mediator than the first experimental procedure, but made it possible to examine the effect of mediator on rate of cell growth while cells were growing logarithmically at a constant rate (Chang, C. S. et al; J. BIOL. CHEM. 257:3650-3654 (1982)).
J. Effect of Endotoxin-Stimulated Macrophage Mediator on the Growth and Differentiation of Friend Cells Growing at a Constant Rate: In order to examine the effect of the macrophage mediator on the growth of Friend cells while they are growing at a constant rate, cells were diluted with fresh medium with or without the mediator every 24 hours to reduce the cell density to 2×105 cells/ml.
Under these conditions of culture, the cells maintain a continuous logarithmic growth at a constant rate (Chang, C.S. et al supra.). The total number of cells that would have formed from the original untreated control culture was 82×106 cells/ml after 96 hours of incubation (FIG. 14). The addition of the macrophage mediator significantly inhibited (˜70%) cell growth. The addition of Me2 SO to the cultures yielded 42×106 cells/ml. This decrease probably reflects the growth cessation which is associated with terminal erythroid differentiation of these cells. (Chang, C. S. supra.; Lo, S. C., Aft, R. and Mueller, G. C., Cancer Res. 41: 864-870 (1981)). Combined addition of Me2 SO and the macrophage mediator produced the most profound growth inhibition (˜90%) of these cells. Heme content in cells treated with the mediator alone was not appreciably affected while the combined treatment with the mediator and Me2 SO brought about ˜40% inhibition of heme formation.
10. A method for preparing a mediator comprising:
A. gathering a sample of macrophage cells from a mammal;
B. incubating a portion of said macrophage cells with a stimulator material associated with an invasive event for a mammal;
C. inducing said macrophage cells to produce said mediator; and
D. recovering a proteinaceous mediator originating from invasive stimuli treated macrophage cells having the following characteristics; capable of suppressing the activity of lipoprotein lipase, acetyl coenzyme A carboxylase and fatty acid Synthetase, and capable of inhibiting the growth and differtiation of erythroid-committed cells.
11. The method of claim 10 wherein said stimulator material comprises endotoxin.
22. The method of claim 21 wherein said mediator is measured by:
A. preparing at least one sample of said mediator from a corresponding number of distinct known invasive stimuli;
B. preparing a corresponding number of antibodies from said mediator samples;
C. placing a detactable label on a material selected from the group consisting of said mediator samples and said antibodies;
D. placing the labeled material from Step C in contact with a biological sample from said mammal in which invasion is suspected; and
E. examining said biological sample for the presence of said labeled material.
23. The method of claim 21 wherein said mediator is measured by:
B. placing a detectable label on said mediator sample;
C. placing the labeled mediator sample in contact with a biological sample from said mammal in which invasion is suspected; and
D. examining said biological sample for the presence of said labeled mediator sample.
24. A method for measuring the activity of a proteinaceous mediator originating from invasive stimuli treated macrophage cells having the following characteristics; capable of suppressing the activity of the anabolic enzymes lipoprotein lipase, acetyl Coenzyme A carboxylase and fatty acid synthetase, and inhibiting the growth and differentiation of erythroid-committed cells, said method comprising;
A. preparing the mediator to be measured from a stimulator material known to be associated with said invasive stimulus;
B. forming a labeled material by placing a detectible label on said mediator;
C. isolating a bioligical sample selected from the group consisting of blood and body fluid, from a mammal suspected of harboring said invasive stimulus;
D. placing said labeled material in contact with said biological sample; and
E. examining said biological sample to locate said labeled material, to thereby determine the activity of said mediator.
25. The method of claim 24 further comprising preparing the antibodies which react with said mediator, which antibodies may be used in said method in the same manner as said mediator.
35. The method of claim 24 wherein said mediator is prepared by:
A. isolating a colony of mammalian macrophage cells;
B. incubating said macrophage cells with said stimulator material for a period of time sufficient for said stimulator material to induce said macrophage cells to produce said mediator; and
C. isolating said mediator from said macrophage cells.
36. A method of testing the ability of a drug to inhibit the activity of a mediator capable of reducing the lipoprotein lipase activity in the nammalian body which comprises culturing 3T3-L1 cells in a growth media containing the mediator, adding the drug under test and thereafter testing lipoprotein lipase activity of the media, said mediator comprising a protein material originating from invasive stimuli treated macrophage cells having the following characteristics; capable of suppressing the activity of the anabolic enzymes lipoprotein lipase, acetyl Coenzyme A carboxylase and fatty acid synthetase, and inhibiting the growth and differentiation of erythroid-committed cells.
38. A test kit for the demonstration of a mediator in serum or an aqueous medium, comprising:
A. a predetermined amount of at least one labeled immunochemically reactive component obtained by the direct of indirect attachment of a mediator or a specific binding partner thereto, to a detectable label, said mediator comprising a protein material originating from invasive stimuli treated macrophage cells having the following characteristics; capable of suppressing the activity of lipoprotein lipase, acetyl Coenzyme A carboxylase and fatty acid synthetase, and inhibiting the growth and differentiation of erythroid-committed cells;
B. other reagents; and
C. directions for use of said kit.
39. The test kit of claim 38 wherein the label is an enzyme.
US06414098 1982-02-22 1982-09-07 Lipoprotein lipase suppression by endotoxin-induced mediator (shock assay) Expired - Lifetime US4603106A (en)
US06792372 US4822776A (en) 1981-09-08 1985-10-29 Lipoprotein lipase suppression by endotoxin-induced mediator (shock assay)
US08207888 US5616688A (en) 1981-09-08 1994-03-07 Macrophage-derived inflammatory mediator (MIP-1α and MIP-1β)
US08285498 US5703206A (en) 1981-09-08 1994-08-03 Macrophage inflammatory protein 2 (MIP-2)
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US08479366 US6046309A (en) 1981-09-08 1995-06-07 Macrophage-derived inflammatory mediator (MIP-1α and MIP-1β)
US08480347 US5817763A (en) 1981-09-08 1995-06-07 Macrophage-derived inflammatory mediator (MIP-1α and MIP-1β)
US08472466 US5989836A (en) 1981-09-08 1995-06-07 Method for measuring the binding sites for macrophage-derived inflammatory mediator (MIP-1α and MIP-1β)
US08473148 US5849873A (en) 1981-09-08 1995-06-07 Macrophage-derived inflammatory mediator (MIP-1 α and MIP-1 β)
US08480342 US5760186A (en) 1981-09-08 1995-06-07 Antibody to macrophage-derived inflammatory mediator (MIP-1α and MIP-1β)
US08473189 US6019969A (en) 1981-09-08 1995-06-07 Composition comprising antibody to macrophage-derived inflammatory mediator (MIP-α 1 and MIP-1β)
US08476378 US5863535A (en) 1981-09-08 1995-06-07 Macrophage-derived inflammatory mediator (MIP-1α and MIP-1β)
US08472753 US6309640B1 (en) 1981-09-08 1995-06-07 Lipoprotein lipase suppression by endotoxin-induced mediator (shock assay)
US08476377 US5741484A (en) 1981-09-08 1995-06-07 Macrophage-derived inflammatory mediator (MIP-1α and MIP-1β)
US35129082 Continuation-In-Part 1982-02-22 1982-02-22
US76685285 Continuation-In-Part 1985-08-16 1985-08-16
US06792372 Division US4822776A (en) 1981-09-08 1985-10-29 Lipoprotein lipase suppression by endotoxin-induced mediator (shock assay)
US10482787 Continuation-In-Part 1987-10-02 1987-10-02
US4603106A true US4603106A (en) 1986-07-29
ID=26997027
US06414098 Expired - Lifetime US4603106A (en) 1982-02-22 1982-09-07 Lipoprotein lipase suppression by endotoxin-induced mediator (shock assay)
US (1) US4603106A (en)
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