JP6708376B2 - IFN-γ and/or IL-17 production inhibitor, and Th1 cell and/or Th17 cell differentiation inhibitor - Google Patents

Description

The present invention relates to an inhibitor of IFN-γ and/or IL-17 production, and an inhibitor of Th1 cell and/or Th17 cell differentiation. Furthermore, the present invention relates to a pharmaceutical composition for treating and/or preventing inflammatory diseases or autoimmune diseases.

Helper T cells, which are the control tower of the immune system, are classified into Th1 cells and Th2 cells, etc., depending on the difference in the production pattern of cytokines, which are intracellular signaling substances.

Th1 cells release interleukin 2 (IL-2) and interferon γ (IFN-γ), enhance the activity of T cells and monocytes, and enhance cellular immunity. Th2 cells release IL-4 and the like, and enhance humoral immunity that enhances antibody production. Naive cells before being differentiated into Th1/Th2 are called Th0 cells. IL-12 secreted by macrophages and IFN-γ secreted by Th1 cells themselves promote differentiation of Th0 cells into Th1 cells.

These Th1/Th2 cells efficiently eliminate pathogens by predominantly differentiating into either one of them depending on the type of infected pathogen. It is considered that when Th1 is dominant, an inflammatory reaction occurs, and when Th2 becomes dominant, an allergic reaction occurs. It is known that excessive Th1 cells exacerbate inflammatory diseases such as multiple sclerosis and inflammatory bowel disease, and autoimmune diseases.

In addition, in recent years, the presence of Th17 cells has been revealed as a T cell subset that does not belong to Th1 or Th2. IL-17 produced by Th17 cells is a type of inflammatory cytokine and is considered to be involved in the pathogenesis of autoimmune diseases. Thus, while IL-17 produced and secreted by Th17 cells acts as a defense mechanism from extracellular bacteria and fungi, its hypersecretion causes rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, psoriasis, systemic It is known to cause inflammatory diseases such as lupus erythematosus, Behcet's disease, and high IgE syndrome and autoimmune diseases (Non-patent documents 1-3).

Therefore, by suppressing the differentiation into Th1 cells and Th17 cells, a preventive and/or therapeutic effect on inflammatory diseases and autoimmune diseases is expected. Currently, IFN-β1A (trade name: Avonex, manufacturer: Biogen Japan Co., Ltd.), ustekinumab (brand name: Stella, manufacturer: Janssen Pharma Co., Ltd.) are drugs that suppress the differentiation of Th1 cells and Th17 cells. Company) is known. In addition, as a natural material, flavonoids have been reported to have an effect of suppressing the differentiation of Th1 cells and Th17 cells (for example, Non-Patent Documents 4-5).

Non-Patent Document 4 reports that administration of a flavonoid, quercetin, suppressed Th cell proliferation and Th1 cell differentiation.

Non-Patent Document 5 reports that administration of the flavonoid Baicalin significantly reduced the number of Th17 cells and reduced the amount of IL-17 produced by Th17 cells.

Zambrano-Zaragoza JF, Romo-Martinez EJ, Duran-Avelar Mde J, Garcia-Magallanes N, and Vibanco-Perez N. International Journal of Inflammation. 2014 Aug 3, http://dx.doi.org/10.1155/2014/ 651503 Bedoya SK, Lam B, Lau K, and Larkin J 3rd. Clinical and Developmental Immunology. 2013 Dec 26, http://dx.doi.org/10.1155/2013/986789 Shabgah AG, Fattahi E, and Shahneh FZ. Postepy Dermatologii i Alergologii. 2014 Aug;31(4):256-61. Muthian G, and Bright JJ, Journal of Clinical Immunology. 2004 December;24(5):542-552. Zou Y, Dai SX, Chi HG, Li T, He ZW, Wang J, Ye CG, Huang GL, Zhao B, Li WY, Wan Z, Feng JS, Zheng XB, Arch Pharm Res. 2014 Oct 1;DOI: 10.1007 /s12272-014-0486-2

As described above, flavonoids have already been reported to suppress the differentiation of Th1 cells and Th17 cells. However, it has not been reported that cinnamic acid derivatives suppress the differentiation of Th1 cells or Th17 cells.

It is an object of the present invention to provide an IFN-γ and/or IL-17 production inhibitor containing a cinnamic acid derivative as an active ingredient, and a Th1 cell and/or Th17 cell differentiation inhibitor. Furthermore, the present invention is an inflammatory disease or autoimmune disease containing a cinnamic acid derivative as an active ingredient (particularly psoriasis, glioma, atherosclerosis, spondyloarthropathy, vitiligo, systemic lupus erythematosus, rheumatoid arthritis). , Inflammatory bowel disease, or multiple sclerosis).

The present inventor has conducted extensive studies to achieve the above-mentioned object, and as a result, cinnamic acid derivatives such as artepiline C, dolpanin, buccarin, clifolin, and caffeic acid suppress the differentiation of Th1 cells and/or Th17 cells. We obtained the finding that it has an action. These effects were also superior to the flavonoid quercetin.

The present invention has been completed through further studies based on these findings. The following IFN-γ and/or IL-17 production inhibitors, Th1 cell and/or Th17 cell differentiation inhibitors and pharmaceuticals A composition is provided.

Item 1. An IFN-γ and/or IL-17 production inhibitor containing, as an active ingredient, at least one cinnamic acid derivative selected from the group consisting of artepiline C, dolpanin, baccaline, clifolin, and caffeic acid.
Item 1-1. Item 2. The production inhibitor according to Item 1, wherein the cinnamic acid derivative is dolpanin.
Item 2. An agent for suppressing Th1 cell and/or Th17 cell differentiation, which comprises, as an active ingredient, at least one cinnamic acid derivative selected from the group consisting of artepiline C, dolpanin, baccaline, clifolin, and caffeic acid.
Item 2-1. Item 3. The differentiation inhibitor according to Item 2, wherein the cinnamic acid derivative is dorpanine.
Item 3. For the treatment and/or prevention of inflammatory diseases or autoimmune diseases, containing at least one cinnamic acid derivative selected from the group consisting of artepiline C, dolpanin, baccaline, clifolin, and caffeic acid as an active ingredient Pharmaceutical composition.
Item 3-1. Item 4. The pharmaceutical composition according to Item 3, wherein the cinnamic acid derivative is dorpanine.
Item 4. Item 3. Item 3 for the treatment and/or prevention of psoriasis, glioma, atherosclerosis, spondyloarthropathy, vitiligo, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, or multiple sclerosis Pharmaceutical composition.

Since the cinnamic acid derivative has an excellent effect of suppressing Th1 cell and Th17 cell differentiation, it is expected to have a preventive or therapeutic effect on diseases that develop or worsen in association with the differentiation of Th1 cells and Th17 cells.

Therefore, according to the present invention, it is possible to provide an inhibitor of IFN-γ and/or IL-17 production, and an inhibitor of Th1 cell and/or Th17 cell differentiation, which comprises a cinnamic acid derivative as an active ingredient. Along with cinnamic acid derivative as an active ingredient, inflammatory disease or autoimmune disease (particularly psoriasis, glioma, atherosclerosis, spondyloarthropathy, vitiligo, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel) A pharmaceutical composition for treating and/or preventing a disease or multiple sclerosis) can be provided.

Further, the cinnamic acid derivative is particularly useful as a component of health foods, supplements, etc. that are orally ingested.

Hereinafter, the present invention will be described in detail.

It should be noted that in the present specification, “comprise” includes the meaning of “essentially consist of” and the meaning of “consist of”.

In cinnamic acid derivative present invention, the cinnamic acid _{(cinnamic acid) (C 6 H} 5 CH = CHCOOH) derivative, preferably a Arutepirin C (artepillin C), Dorupanin (Drupanin), Bakkarin (Baccharin), Kuriforin ( culifolin) and caffeic acid, with dolpanine being particularly preferred. The cinnamic acid derivative may be one type alone or a combination of two or more types.

The structural formulas of artepirin C, dolpanine, buccarin, clifolin, and caffeic acid are shown below.

In the present invention, the cinnamic acid derivative may be either in an isolated or purified state (crude extract) or in an isolated or purified state.

In the present invention, the cinnamic acid derivative may be used as a self-prepared product or a commercially available product. Here, the method for self-preparing the cinnamic acid derivative is not particularly limited, and examples thereof include a method of extracting from a plant and a natural product containing the cinnamic acid derivative, and a method of chemically synthesizing the same.

The plant containing the cinnamic acid derivative is not particularly limited, and examples thereof include plants of the Asteraceae family such as alekulin. The natural product is not particularly limited, and examples thereof include propolis containing a cinnamic acid derivative. The propolis containing a cinnamic acid derivative may be derived from any production source/plant such as Brazil, China, European countries, Oceania, and America.

The cinnamic acid derivative may be used in a free state or a salt state. Examples of the salt include salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, and ethanolamine; basic amino acids such as lysine, ornithine, and arginine. Salts and ammonium salts are mentioned. The salt may be an acid addition salt, and specific examples of the salt include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid; formic acid, acetic acid, Organic acids such as propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methane sulfonic acid, ethane sulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid Acid addition salts may be mentioned. The cinnamic acid derivative also includes hydrates, solvates, crystal polymorphs, and the like.

It is desirable to administer or apply the active ingredient of the present invention to humans, but it is also possible to administer or apply to animals/pets such as dogs and cats and livestock such as horses, cattle, pigs and poultry as well as inflammatory diseases or self-treatment. To prevent and/or treat immune diseases (particularly psoriasis, glioma, atherosclerosis, spondyloarthropathy, vitiligo, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, or multiple sclerosis) it can. The active ingredient of the present invention can be used as an oral ingestion preparation or a patch. The active ingredient of the present invention is usually used in the form of a liquid preparation or a solid preparation suitable for oral administration or application.

In determining the dose of the active ingredient of the present invention, the minimum effective concentration in the test examples described below is used as an index.

IFN-γ and/or IL-17 production inhibitor The IFN-γ and/or IL-17 production inhibitor of the present invention is a cinnamic acid derivative (preferably artepiline C, dolpanine, buccarin, clifolin, and cafe An acid, more preferably dolpanine) is used as an active ingredient.

The IFN-γ and/or IL-17 production inhibitor of the present invention contains an additional component unless the cinnamic acid derivative's IFN-γ and/or IL-17 production inhibitory action is prevented. Good. The proportion of the cinnamic acid derivative in the IFN-γ and/or IL-17 production inhibitor containing such an additional component may be, for example, 0.0001 to 98% by weight.

The IFN-γ and/or IL-17 production inhibitor of the present invention is not particularly limited in its form, for example, powder, granules, tablets, capsules, sticks, pastes, gels, It may have a liquid form, a suspension form, an emulsion form, an ointment form or the like.

The IFN-γ and/or IL-17 production inhibitor of the present invention has an immunosuppressive action based on the IFN-γ and/or IL-17 production inhibitory action, and therefore extracellular bacterial elimination, neutrophil inflammation, It can be suitably used as an active ingredient of a drug, a quasi drug, and a food composition for treating and/or preventing an inflammatory disease or an autoimmune disease.

The IFN-γ and/or IL-17 production inhibitor of the present invention is a food or drink for the purpose of health, maintenance of health, promotion, etc., such as health foods, functional foods, foods with functional claims, dietary supplements, supplements. , Foods for specified health uses, or foods with nutrient function claims are also included. The IFN-γ and/or IL-17 production inhibitor of the present invention also includes the meaning of an additive that imparts an IFN-γ and/or IL-17 production inhibitory effect.

In the above foods, if necessary, excipients, brighteners, minerals, vitamins, flavonoids, quinones, polyphenols, amino acids, nucleic acids, essential fatty acids, cooling agents, binders, sweeteners, disintegration Agents, lubricants, colorants, fragrances, stabilizers, preservatives, sustained release regulators, surfactants, solubilizers, wetting agents and the like can be added.

The dosage unit form for use as a supplement is not particularly limited and may be appropriately selected, and examples thereof include tablets, capsules, granules, liquids, powders and the like.

The proportion of the cinnamic acid derivative contained in the above food can be, for example, a concentration of 0.0001 to 80% by weight.

The intake amount of the above foods can be appropriately set according to various conditions such as the weight, age, sex, and symptoms of the ingestor.

Th1 cell and/or Th17 cell differentiation inhibitor The Th1 cell and/or Th17 cell differentiation inhibitor of the present invention is a cinnamic acid derivative (preferably artepirin C, dolpanin, buccarin, clifolin, and caffeic acid, more preferably Is characterized by containing dolpanin) as an active ingredient.

The Th1 cell and/or Th17 cell differentiation inhibitor of the present invention may contain an additional component as long as the cinnamic acid derivative's Th1 cell and/or Th17 cell differentiation inhibitory action is not hindered. The proportion of the cinnamic acid derivative in the Th1 cell and/or Th17 cell differentiation inhibitor containing such an additional component may be, for example, 0.0001 to 98% by weight.

The Th1 cell and/or Th17 cell differentiation inhibitor of the present invention is not particularly limited in its form, for example, powder, granules, tablets, capsules, sticks, pastes, gels, liquids, It may have a formulation form such as suspension, emulsion or ointment.

The Th1 cell and/or Th17 cell differentiation inhibitor of the present invention has an immunosuppressive action based on the Th1 cell and/or Th17 cell differentiation inhibitory action, so that it is a condition specific to Th1 cell or Th17 cell differentiation, extracellular. It can be suitably used as an active ingredient of a drug, a quasi drug, and a food composition for treating and/or preventing bacterial elimination, neutrophil inflammation, inflammatory disease or autoimmune disease.

The Th1 cell and/or Th17 cell differentiation inhibitor of the present invention is a food or drink for the purpose of health, maintenance of health, promotion, etc., such as health foods, functional foods, functionally labeled foods, dietary supplements, supplements, specifics. It also includes the meaning of food for health use or food with nutritional function. The Th1 cell and/or Th17 cell differentiation inhibitor of the present invention also includes the meaning of an additive that imparts a Th1 cell and/or Th17 cell differentiation inhibitory effect.

In the above foods, if necessary, excipients, brighteners, minerals, vitamins, flavonoids, quinones, polyphenols, amino acids, nucleic acids, essential fatty acids, cooling agents, binders, sweeteners, disintegration Agents, lubricants, colorants, fragrances, stabilizers, preservatives, sustained release regulators, surfactants, solubilizers, wetting agents and the like can be added.

The dosage unit form for use as a supplement is not particularly limited and may be appropriately selected, and examples thereof include tablets, capsules, granules, liquids, powders and the like.

The proportion of the cinnamic acid derivative contained in the above food can be, for example, a concentration of 0.0001 to 80% by weight.

The intake amount of the above food can be appropriately set according to various conditions such as the weight, age, sex, and symptoms of the ingestor.

Pharmaceutical Composition The pharmaceutical composition of the present invention is characterized by containing a cinnamic acid derivative (preferably artepiline C, dolpanin, buccarin, clifolin, and caffeic acid, more preferably dolpanin) as an active ingredient. Moreover, the pharmaceutical composition of the present invention is administered or applied to mammals including humans.

When prepared as a pharmaceutical composition, a cinnamic acid derivative together with a non-toxic carrier, diluent or excipient acceptable in medicine, tablets (plain tablet, sugar-coated tablet, effervescent tablet, film-coated tablet, chewable tablet, lozenge) Etc.), capsules, pills, powders (powder), fine granules, granules, solutions, suspensions, emulsions, syrups, pastes, injections (distilled water or amino acid infusion or It may be prepared in the form of an ointment or the like by incorporating it into an infusion such as an electrolyte infusion to prepare a liquid preparation), and prepare a medicinal preparation.

The content of the cinnamic acid derivative in the pharmaceutical composition of the present invention may be appropriately selected from the range of 0.000001 to 99% by weight, preferably 0.00001 to 99% by weight, more preferably 0.0001 to 98% by weight in the total amount of the pharmaceutical composition. It is possible.

The dose or application amount of the pharmaceutical composition of the present invention can be appropriately determined according to various conditions such as the body weight, age, sex and symptoms of the patient.

The pharmaceutical composition and food of the present invention are inflammatory diseases or autoimmune diseases (particularly psoriasis, glioma, atherosclerosis, spondyloarthropathy, vitiligo, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, Or, it is useful for the treatment and/or prevention of multiple sclerosis).

Examples will be given below to explain the present invention in more detail. However, the present invention is not limited to these examples.

Test example 1
The cinnamic acid derivative was examined for its Th1 cell differentiation inhibitory effect according to the following procedure. In either test, the frequency of Th1 cells induced to differentiate by IL-12 stimulation or the amount of IFN-γ produced in the Th1 cells induced to differentiate was used as the standard, and the concentration at which the differentiation state was lower than that was the most effective. The concentration was used.

(i) IL-12 stimulation-induced IFN-γ production suppression Healthy C57BL/6J mice (6-8 weeks old, male, Japan SLC, Inc.) were euthanized, and their spleens were excised. A splenocyte suspension (4×10 ⁶ cells/ml) was prepared. The CD4+ T cell fraction was purified using the CD4 ⁺ T cell Isolation Kit (Militenyi Biotec Inc., Auburn, CA, USA).

Anti-mouse CD3/antibody and anti-mouse CD28 antibody (both 1 μg/ml, BioLegend, San Diego, CA, USA) were immobilized on a culture plate at 10 ng/ml mouse recombinant IL-12p70 (R&D Systems, Minneapolis, MN). , USA), test sample (final concentration 50 nM, 12.5 nM, 3.1 nM, 0.8 nM), and splenocyte suspension (2×10 ⁶ cells/ml) were added, and the mixture was cultured at 37° C. for 5 days.

An anti-mouse IFN-γ monoclonal antibody (1/200, BioLegend, Inc., San Diego, CA, USA) was dissolved as a primary antibody in a carbonate buffer (0.05 M NaHCO ₃ ), and 50 μl/well each was added to a 96-well microplate. (Nunc Immunoplate Maxisop, Thermo Fisher Scientific, Inc., Roskilde, Denmark), and immobilized (4°C, overnight). A blocking solution (1% sucrose, 1% bovine serum albumin (BSA)/phosphate buffered saline (PBS)-Tween 20 solution) was added at 100 μl/well, and blocking was performed at room temperature for 90 minutes. After washing the plate 3 times with PBS containing 0.05% Tween 20 (PBS-T), serially diluted solution of standard substance (mouse recombinant IFN-γ 1000 pg/ml, BioLegend, Inc.) of known concentration and culture medium (Sample) was added to the plate and reacted for 120 minutes at room temperature.

Then, the plate was washed 3 times with PBS-T. A biotin-labeled anti-mouse IFN-γ monoclonal antibody (1/200, BioLegend, Inc.) was added at 50 μl/well, and the mixture was reacted for 120 minutes at room temperature. After the reaction, the plate was washed 3 times with PBS-T, 50 μl/well of peroxidase-labeled streptavidin (1/1000, BioLegend, Inc.) was added, and the mixture was reacted at room temperature for 90 minutes. After the reaction, wash 3 times with PBS-T, add 50 μl/well of substrate solution (Sure Blue TMB Microwell Peroxidase Substrate, KPL, MD, USA) to react, and then stop the enzyme reaction in all wells. 0.5 M sulfuric acid was added to each well at 50 μl/well. Immediately after the reaction was stopped, the absorbance (450 nm) was measured with Microplate Reader Model 680 (Bio-Rad Laboratories, Inc., CA, USA).

As a result of measuring the amount of IFN-γ in the culture supernatant, the flavonoid quercetin, which has been reported to suppress Th1 cell differentiation (Reference 1), showed a minimum effective concentration of 50 nM. On the other hand, the cinnamic acid derivatives p-coumaric acid, artepirin C, dolpanine, and caffeic acid showed the minimum effective concentration of 0.8 nM, and buccarin showed the minimum effective concentration of 3.1 nM, which showed stronger inhibitory effect on IFN-γ production than quercetin. (Table 1).

(ii) Th-12 differentiation inhibitory effect by IL-12 stimulation
The T cells differentiated into Th1 cells by the method described in (i) were collected, phorbol myristate acetate (PMA, 0.05 μg/ml) and ionomycin (1 μg/ml) were added, and the mixture was cultured at 37°C for 4 hours. And induced cytokine production. Brefeldin A (BFA, 5 μg/ml) was added as a protein secretion inhibitor during the last 2 hours of this culture. After culturing, cells were collected and stained with a fluorescently labeled antibody. First, cell surface antigen CD4 was labeled with spectral red (SPRD)-labeled anti-mouse CD4 rat antibody (Beckman Coulter, Inc., Tokyo, Japan).

Subsequently, the cells were fixed with 4% paraformaldehyde and permeabilized with 0.3% saponin. After permeabilization, staining was performed with R-phycoerythrin (PE)-labeled anti-mouse IFN-γ rat antibody (BioLegend, Inc.). In addition, PE-labeled rat IgG antibody (eBioscience) and SPRD-labeled rat IgG antibody (eBioscience) were used as negative controls (isotype control antibody) for staining. The stained cells were measured with a flow cytometer EPICS ALTRA (Beckman Coulter, Inc., Tokyo, Japan), and the data was analyzed by EXPO32 Analysis.

As a result, the minimum effective concentration of quercetin was 12.5 nM, whereas dolpanin showed the minimum effective concentration of 3.1 nM, and a stronger Th1 cell inhibitory action than quercetin was observed (Table 2).

Test example 2
The cinnamic acid derivative was examined for its inhibitory effect on Th17 cell differentiation according to the following procedure. In all of the tests, Th17 cell differentiation induced by IL-6 and TGF-β stimulation was used as a standard, and a component having a differentiation state lower than that was judged to have a Th17 differentiation inhibitory action.

(i) Inhibition of IL-17 production by IL-6 and TGF-β stimulation A splenocyte suspension was prepared in the same manner as in Test Example 1(i). IL-6 (20 ng/ml; Wako Pure Chemical Industries, Ltd, Osaka) was added to a culture plate immobilized with anti-mouse CD3 antibody and anti-mouse CD28 antibody (both 1 μg/ml, BioLegend, San Diego, CA, USA). , Japan), TGF-β (1 ng/ml; Peprotech, Inc., NJ, USA), test sample (final concentration 50 nM, 12.5 nM, 3.1 nM, 0.8 nM), and splenocyte suspension (2 × 10 ⁶ cells/ml) was added and the cells were cultured at 37°C for 5 days. Then, ELISA was performed by the method described in Test Example 1(i) to measure the amount of IL-17 in the culture supernatant. At that time, anti-mouse IL-17 monoclonal antibody (1/200, BioLegend, Inc., San Diego, CA, USA) was used as the primary antibody, and biotin-labeled anti-mouse IL-17 monoclonal antibody (1/200, BioLegend was used as the secondary antibody. , Inc., San Diego, CA, USA), and mouse recombinant IL-17A 1000 pg/ml (BioLegend, Inc.) was used as a standard substance.

As a result of measuring the amount of IL-17 in the culture supernatant, the flavonoid quercetin, which has been reported to suppress the production of IL-17 (Reference 2), showed a minimum effective concentration of 12.5 nM. On the other hand, the cinnamic acid derivatives, dorupanin, buccarin, and clifolin showed a minimum effective concentration of 0.8 nM, and p-coumaric acid, artepillin C, and caffeic acid showed a minimum effective concentration of 3.1 nM, which is a stronger inhibitory effect on IL-17 production than quercetin. Was observed (Table 3).

(ii) Inhibition of Th17 differentiation by IL-6 and TGF-β stimulation
T cells that had been induced to differentiate into Th17 cells in (i) were collected, and the number of IL-17-producing cells (the number of Th17 cells) was measured by the method described in Test Example 1 (ii). For staining after permeabilization, R-phycoerythrin (PE)-labeled anti-mouse IL-17 rat antibody (BioLegend, Inc.) was used.

As a result, quercetin, artepirin C, dolpanin, and caffeic acid showed a minimum effective concentration of 3.1 nM, and the cinnamic acid derivative showed the same Th17 cell differentiation inhibitory action as quercetin (Table 4).

References
1) Pan L, Chen Z, Wang L, Chen C, Li D, Wan H, Li B, Shi G, Deubiquitination and stabilization of T-bet by USPIO, Biochem Biophys Res Commun.Volume 449(3), July(2014) ), 289-294.
2) Milenkovic M, Arsenovic-Ranin N, Stojic-Vukanic Z, Bufan B, Vucicevic D, Jancic I, Quercetin ameliorates experimental autoimmune myocarditis in rats. J Pharm Pharmaceut Sci. Volume 13(3), (2010), 311-319 .
Prescription example Hereinafter, the prescription example of this invention is shown.

Prescription example 1
200 g of ethanol solution containing 31.2 g of artepiline C, dolpanine, buccarinic acid and p-coumaric acid is sprayed on 1 kg of lactose, dried, pulverized, filled into a hard capsule, and artepiline C, dolpanine, buccarin, and p- A coumaric acid-containing capsule was obtained.

Prescription example 2
250 g of starch syrup, 300 g of sugar, and 50 ml of water were heated and dissolved, and 50 g of an ethanol solution containing dolpanine was added. In particular, it was molded into a proper size to obtain a dolpanin-containing candy.

Prescription example 3
Ethanol solution containing dolpanine 0.5 g
Ascorbic acid 300 mg
10 g honey
Lemon juice 10 ml
Water Appropriate amount The above ingredients were mixed to obtain a total amount of 50 ml of a drink containing dolpanine.

Prescription example 4
Powders having the following formulation were uniformly mixed and used as a tablet supplement of 160 mg using a tableting machine according to a conventional method.
Spray-dried product of ethanol solution containing dolpanine 10 mg
Dry beer yeast powder 50 mg
Reduced maltose 75 mg
Sucrose fatty acid ester 20 mg
Cellulose 5 mg
Prescription example 5
75 g of an ethanol solution containing dolpanine was pulverized. To this, 32.15 g of cornstarch as a coating agent was added (coated) to obtain 107.15 g of dolpanin-containing coated granules. The coating ratio of this granule is 0.3.

Prescription example 6
Soybean oil (150 mg), beeswax (20 mg), and glycerin fatty acid ester (30 mg) were mixed with ethanol solution (50 mg) containing dolpanine according to a conventional method and filled into gelatin soft capsules to give granular health food (oral composition).

Claims (2)

An IL-17 production inhibitor comprising, as an active ingredient, at least one cinnamic acid derivative selected from the group consisting of artepiline C, dolpanin, baccaline, clifolin, and caffeic acid. A Th17 cell differentiation inhibitor containing, as an active ingredient, at least one cinnamic acid derivative selected from the group consisting of artepiline C, dolpanin, baccaline, clifolin, and caffeic acid.