JPWO2018221562A1 - Composition for suppressing IL-8 production from activated T cells - Google Patents

Abstract

It has been found that dopamine D2-like receptor agonists act on dopamine D2-like receptors in activated Th cells and suppress the production of interleukin 8 (IL-8).

Description

  The present invention relates to a composition for suppressing IL-8 production from activated T cells, which comprises a dopamine D2-like receptor agonist as an active ingredient.

  Helper T cells, which play a central role in acquired immunity, are classified as Th1 (type 1 helper T cells), Th2 (type 2 helper T cells), Th17 (type 17 helper T cells), etc. due to differences in cytokines produced, etc. Be done.

  Conventionally, it is thought that an abnormality in Th1 / Th2 balance is involved in the onset of various immune related diseases, for example, balance bias to Th1 cells is caused by chronic inflammatory diseases such as rheumatoid arthritis, organ specific autoimmunity Diseases (eg, multiple sclerosis, type 1 diabetes, inflammatory bowel disease, glomerulonephritis, hepatitis, liver injury, autoimmune hemolytic anemia, leukopenia, thrombocytopenia, demyelinating disease, Hashimoto's thyroiditis, It is considered to be involved in malignant anemia, psoriasis, etc., and balance bias to Th2 cells is considered to be involved in allergic diseases and many systemic autoimmune diseases. On the other hand, Th17 cells are exclusively involved in the aggravation of autoimmune inflammation by producing IL-17, and in particular, the aforementioned type 1 diabetes, inflammatory bowel disease, psoriasis, multiple sclerosis, and joints It is believed that rheumatism is strongly suspected due to this Th17 bias (Non-patent Document 1).

  There are many factors involved in the acquired immune system in a complex manner, and it is still unclear whether any immune related diseases involve Th1 bias, Th2 bias, or Th17 bias, but there are still many unclear points. Have already found that the function of dopamine (DA) is largely involved in the Th1 / Th2 / Th17 differentiation induction mechanism via dendritic cells (Patent Document 1). In this report, specifically, the action of an antagonist on a dopamine D1-like receptor on dendritic cells suppresses the synthesis and storage of dopamine in dendritic cells, and as a result, Th17 of naive T cells. It has been shown that induction of differentiation into cells or Th2 cells is suppressed, and induction of differentiation into Th1 cells is promoted. Furthermore, when the antagonist acts on a dopamine D2-like receptor on dendritic cells, synthesis and storage of dopamine in dendritic cells are promoted, and as a result, induction of differentiation of naive T cells to Th1 cells is suppressed It has also been shown that induction of differentiation into Th2 cells is promoted.

  On the other hand, the present inventors show that Orengedokuto (Kampo formula containing ougonin as a main component) suppresses the induction of differentiation of Th17 cells, and that berberine suppresses the induction of differentiation of Th17 cells or Th1 cells. Have also been reported (Non-patent documents 2 to 4). However, all of these findings are intended to control the induction of differentiation from naive T cells to Th cells, and not to control functions of already differentiated and activated Th cells.

Patent No. 5442256

Batten, M et al. Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nat Immunol. 2006.7: 929-936. Takagi, R. et al., Th17 selective inhibitory action of Oren-gedoku-to and its ameliorating action in neutrophilic airway inflammation model, the clinic of allergy 34: 66-68, 2014 Takagi, R. et al. Wogonin attenuated ovalbumin antigen-induced neutrophilic airway inflammation by inhibiting Th17 differentiation. Int. J. Inflamm. , Vol. 2014, Article ID 571508, 8 pages. Kawano, M. et al. Berberine is a dopamine D1-, D2-like receptor antagonist and ameliorates experimentally induced colitis by suppressing innate and adaptive immunity responses. J. Neuroimmunol. 289: 43-55, 2015.

  The present invention has been made in view of the above-mentioned prior art, and its object is to provide a composition capable of acting on the dopamine receptor of activated Th cells to control the function of the cells. is there.

  As a result of intensive studies to solve the above problems, the present inventor has found that tannic acid, gallic acid and gallic acid esters of catechins have an agonist activity at the dopamine D 2 receptor. .

  In addition, when cytokine production of each Th cell was analyzed and the effect of the dopamine D2-like receptor agonist on the cytokine production was evaluated, the dopamine D2-like receptor agonist acted on the dopamine D2-like receptor in the activated Th cells. And suppressed the production of interleukin 8 (IL-8), an inflammation-related mediator known as a neutrophil chemotactic factor.

  Furthermore, the present inventors examined the effect of a dopamine D2-like receptor agonist using model animals of various diseases associated with neutrophilic inflammation, and found that neutrophilic airway inflammation, psoriasis, ulcerative colon The inventors have found that each model animal of inflammation and periodontal disease has an effect of treating or ameliorating the disease, and has completed the present invention.

  Thus, the present invention relates to the use of a dopamine D2-like receptor agonist to suppress the production of IL-8 in activated Th cells, and more particularly, to provide:

  (1) A composition for suppressing IL-8 production of activated helper T cells, which comprises a dopamine D2-like receptor agonist as an active ingredient.

  (2) The composition according to (1), wherein the dopamine D2 like receptor agonist is tannic acid, gallic acid, catechin or its gallate, ropinirole, or pramipexole.

  (3) The composition according to (1) or (2), wherein the activated helper T cells are Th1 cells or Th17 cells.

  (4) The composition according to any one of (1) to (3), which is used for the treatment or amelioration of neutrophilic inflammation.

  Neutrophilic airway inflammation including neutrophilic bronchial asthma, periodontal disease, psoriasis, severe atopic dermatitis, acne vulgaris, endometriosis, chronic sinusitis, various other autoimmune diseases, etc. There are many pathological conditions that are mainly composed of neutrophilic inflammation. However, no specific drug has been known until now. Corticosteroids are specific agents of eosinophilic inflammation, not specific agents of neutrophilic inflammation. The composition of the present invention exerts an effect by a novel mechanism that targets the dopamine D2-like receptor on activated Th cells and suppresses IL-8 production of the cells, and further, Such side effects are considered not to be a problem. Tannic acid, gallic acid, catechins or their gallic acid esters are natural components contained in various plants, and are particularly high in safety. According to the present invention, it is possible to effectively and safely treat or ameliorate a condition (in particular, neutrophilic inflammation) caused by the production of IL-8 from activated Th cells.

It is a graph which shows the result of having detected RC50 with respect to the dopamine D2 receptor of tannic acid. It is the graph which quantified specific cytokine (IFNgamma, IL-5, or IL-17) production and IL-8 production in each Th cell clone, and showed the correlation. The graph showing the results of evaluating the influence on IL-8 production by coexistence of a known dopamine D2-like receptor agonist (pramipexole and ropinirole) in a system in which peripheral blood mononuclear cells (PMBC) are cocultured with Candida antigen is there. It is a graph which shows the result of having made tannic acid coexist in the system which cocultures a peripheral blood mononuclear cell (PMBC) with a Candida antigen, and evaluating the influence on IL-8 production. It is a graph which shows the effect of the dopamine D2-like receptor agonist in a neutrophilic airway inflammation model. Pramipexole and ropinirole were used as dopamine D2-like receptor agonists. Fig. 5 is a graph showing the effect of a dopamine D2-like receptor agonist in a psoriasis model. As dopamine D2 like receptor agonists, A used pramipexole and tannic acid, and B used tannic acid and gallic acid. It is a graph which shows the effect (weight loss suppression) of a dopamine D2 like receptor agonist in a ulcerative colitis model. Ropinirole was used as a dopamine D2-like receptor agonist. It is a graph which shows the effect (weight loss suppression) of a dopamine D2 like receptor agonist in a ulcerative colitis model. Tannic acid was used as a dopamine D2-like receptor agonist. It is a graph which shows the effect (constriction inhibitory effect of a intestine) of the dopamine D2-like receptor agonist in a ulcerative colitis model. Tannic acid was used as a dopamine D2-like receptor agonist. It is a graph which shows the effect of the dopamine D2-like receptor agonist in a periodontal disease model. Tannic acid was used as a dopamine D2-like receptor agonist.

  The present invention provides a composition for suppressing IL-8 production of activated helper T cells, which comprises a dopamine D2-like receptor agonist as an active ingredient.

  There are five subtypes of D1 to D5 in "dopamine receptor", and it is generally known that they have a function to transmit signals into cells in conjugation with G protein. Among them, the dopamine D2 receptor, the dopamine D3 receptor, and the dopamine D4 receptor are collectively referred to as "dopamine D2-like receptors", and their activation promotes the degradation of intracellular cAMP, resulting in intracellular cAMP concentration decreases. The typical amino acid sequence of human-derived dopamine D2 receptor is shown in NCBI Reference Sequence: NP_000786.1 or NCBI Reference Sequence: NP_057658.2, and the typical amino acid sequence of human-derived dopamine D3 receptor is NCBI The typical amino acid sequence of human-derived dopamine D4 receptor is disclosed in NCBI Reference Sequence: NP_000788.2, respectively. "Dopamine D2-like receptor agonist" means a compound that binds to a dopamine D2-like receptor to agonize such signal transduction, such as ropinirole (requip), pramipexole (bi-cyflor), bromocriptine (parrodel And Pergolide (Permax), Cabergoline (Kabasar), Rotigotine (Neuplo), etc., but not limited thereto. In the present invention, since tannic acid, gallic acid, catechins and gallic acid esters thereof are found to be dopamine D2 receptor agonists, these also correspond to the “dopamine D2-like receptor agonists” of the present invention. included. Examples of catechins and gallic acid esters thereof include catechins, epicatechins, gallocatenins, epigallocatechines, epicatechin gallates, gallocatenins gallates, and epigallocatechin gallates. Whether a certain compound is a dopamine D2-like receptor agonist can be evaluated, for example, by an assay using Ca concentration or cAMP concentration as an indicator, as described in this example.

  In the present invention, “activated helper T cells” are helper T cells differentiated by recognizing specific antigens via T cell receptors, and include so-called effector T cells and memory T cells. Examples of "helper T cells" to which the present invention is applied include Th1 cells, Th2 cells, and Th17 cells, which can be distinguished by specific cytokine production. Specific cytokines include interferon gamma (IFNγ) and IL-2 in Th1 cells, IL-4, IL-5, and IL-13 in Th2 cells, and in Th17 cells IL-17 is mentioned. According to the composition of the present invention, helper T cells targeted for suppressing IL-8 production are preferably Th1 cells and Th17 cells.

  The composition of the present invention may be in the form of a pharmaceutical composition (pharmaceutical, quasi-drug, animal medicine, etc.), food and drink, or a reagent used for research purpose (eg, in vivo experimental purpose, etc.).

  The composition of the present invention can be used to treat or ameliorate a condition resulting from IL-8 production of activated T cells. Since IL-8 is an inflammation-related mediator known as a major neutrophil chemotactic factor, the composition of the present invention can be suitably used in the treatment or amelioration of neutrophilic inflammation. The composition of the present invention is, for example, neutrophilic airway inflammation including neutrophilic bronchial asthma, periodontal disease, psoriasis, ulcerative colitis, severe atopic dermatitis, acne vulgaris, endometriosis Treatment or amelioration of various diseases such as chronic rhinosinusitis and various other autoimmune diseases (eg, rheumatoid arthritis, multiple sclerosis, type 1 diabetes, nephritis), particularly among the symptoms of these diseases It can be applied to the treatment or amelioration of bulbar inflammation. Here, "treatment or amelioration of neutrophilic inflammation" is intended to include treatment or amelioration of various symptoms or morphological changes caused by neutrophilic inflammation.

  When the composition of the present invention is used as a pharmaceutical composition, the dosage form is not particularly limited as long as it contains a dopamine D2-like receptor agonist as an active ingredient. The pharmaceutical composition of the present invention can be formulated into various dosage forms by known pharmaceutical methods.

  The dosage form of the pharmaceutical composition is not particularly limited and can be appropriately selected according to the desired administration method, for example, oral solid preparation (tablet, coated tablet, granule, powder, capsule, etc.) Oral solutions (internal solutions, syrups, elixirs, etc.), external preparations (suppositories, ointments, patches, gels, creams, external powders, sprays, inhalants), injections (solutions, suspensions) Liquid, solid solution for daily use dissolution, etc., other oral agents (gum, troche, sublingual tablet, buccal tablet, adhesive), oral spray, semisolid for oral cavity, toothpaste, mouthwash etc Can be mentioned.

  As an oral solid agent, for example, an additive such as a binder, a disintegrant, a lubricant, a coloring agent, a flavoring / flavoring agent and the like is optionally added to a dopamine D2-like receptor agonist, It can be manufactured by a conventional method.

  As the excipient, for example, lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid and the like can be mentioned. As the binder, for example, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, polyvinylpyrrolidone and the like can be mentioned. . As the disintegrant, for example, dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, lactose and the like can be mentioned. As the lubricant, for example, purified talc, stearate, borax, polyethylene glycol and the like can be mentioned. Examples of the colorant include titanium oxide and iron oxide. Examples of flavoring agents include sucrose, orange peel, citric acid, tartaric acid and the like.

  As an oral liquid preparation, for example, additives such as a flavoring agent, a buffer, a stabilizer and the like can be added to a dopamine D2-like receptor agonist, and it can be manufactured by a conventional method.

  Examples of flavoring agents include sucrose, orange peel, citric acid, tartaric acid and the like. As a buffer, sodium citrate etc. are mentioned, for example. As the stabilizer, for example, tragacanth, gum arabic, gelatin and the like can be mentioned.

  As a suppository, for example, a known carrier for suppository formulation such as polyethylene glycol, lanolin, cacao butter, fatty acid triglyceride and an interface such as tween (TWEEN (registered trademark) if necessary, to a dopamine D2-like receptor agonist After adding an activator etc., it can manufacture by a conventional method.

  As an ointment, for example, a known base, a stabilizer, a wetting agent, a preservative and the like can be mixed with a dopamine D2-like receptor agonist and mixed and manufactured by a conventional method.

  As the base, for example, liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, paraffin and the like can be mentioned. As the preservative, for example, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate and the like can be mentioned.

  As a patch, for example, a cream, a gel, a paste and the like as an ointment can be applied to a known support in a usual manner and manufactured. Examples of the support include cotton, cotton wool, woven fabric of chemical fibers, nonwoven fabric, films of soft vinyl chloride, polyethylene, polyurethane and the like, and foam sheets.

  As an injection, for example, a pH regulator, a buffer, a stabilizer, a tonicity agent, a local anesthetic and the like are added to a dopamine D2-like receptor agonist, and subcutaneous, intramuscular, and intravenous are used according to a conventional method. Injections for internal use can be produced.

  As a pH regulator and a buffer, for example, sodium citrate, sodium acetate, sodium phosphate and the like can be mentioned. As a stabilizer, sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid etc. are mentioned, for example. Examples of tonicity agents include sodium chloride and glucose. As the local anesthetic, for example, procaine hydrochloride, lidocaine hydrochloride and the like can be mentioned.

  The preparation to be applied to the oral cavity can also be formulated by known pharmaceutical methods according to the properties thereof.

  When the composition of the present invention is used as a pharmaceutical composition, one or more kinds effective for suppressing IL-8 production of activated helper T cells (preferably, treatment of neutrophilic inflammation) Other ingredients can be blended. It may also be used in combination with other pharmaceutical compositions effective for this purpose.

  The administration target of the pharmaceutical composition is not particularly limited and may be appropriately selected depending on the purpose. Examples thereof include human, mouse, rat, cow, pig, monkey and the like. The administration method can be appropriately selected depending on the dosage form and the like, and examples thereof include oral administration, external administration, and administration by injection. The dose can be appropriately selected according to the type, age, body weight, sex, symptoms and the like of the administration subject, and for example, as the amount of dopamine D2-like receptor agonist which is an active ingredient per day for human adults, For example, an amount selected in the range of 0.04 to 500 mg is considered to be preferred. The frequency of administration is not particularly limited, and can be appropriately selected according to the purpose. For example, the dose per day may be administered once a day, or may be divided into a plurality of times You may Also, it may be administered, for example, 1 to 4 times a week, not daily.

  When the composition of the present invention is used as a food or drink, the food or drink may be, for example, a health food, a functional food, a food for specified health use, a nutritional supplement, a food for sick people, or a food additive. Specific examples of the food and drink include liquids such as drinks, soups, milk drinks, soft drinks, tea drinks, alcoholic beverages, jelly drinks, functional drinks, etc .; oil components such as edible oils, dressings, mayonnaise and margarine Products including; Carbohydrate-containing foods such as rice, noodles and bread; Livestock processed foods such as ham and sausages; Fisheries processed foods such as kamaboko, dried fish and salted fish; Vegetable processed foods such as pickles; Solid foods; Fermented foods such as miso and fermented beverages; Western confectioneries, Japanese confectioneries, candies, gums, various kinds of confectioneries such as gummi, frozen desserts, frozen desserts; Instant foods such as instant miso soup and microwave compatible foods can be mentioned. Furthermore, health food and drink prepared in powder, chew, tablet, capsule, liquid, paste or jelly form can also be mentioned.

  The production of the food and drink in the present invention can be carried out by a production technique known in the art. In the food and drink, one or more components effective for suppressing IL-8 production of the activated helper T cells (preferably, ameliorating neutrophilic inflammation) may be blended. Moreover, you may be set as multifunctional food-drinks by combining with the other component or other functional food which exhibits the function for this purpose.

  The food and drink can be appropriately selected depending on the purpose, and examples include humans, mice, rats, cows, pigs, monkeys and the like. The amount of intake can be appropriately selected according to the type, age, weight, sex, symptoms and the like of the subject to be ingested, for example, as the amount of dopamine D2-like receptor agonist which is an active ingredient per day for human adults. For example, an amount selected in the range of 0.04 to 500 mg is considered to be preferred. The intake frequency can be appropriately selected according to the purpose. For example, the intake per day may be taken once a day, or may be divided into multiple times. Also, it may be taken, for example, 1 to 4 times a week instead of every day.

  The compositions of the present invention may be in the form of being included in a particular device. Accordingly, the present invention provides a device comprising the above composition. There is no particular limitation on the form of the device, and it depends on the purpose of the composition of the present invention. For example, for the purpose of treating or ameliorating neutrophilic inflammation in periodontal disease, the composition of the present invention is in the form contained in dental floss, interdental brush, interdental brush sponge product, toothpick and the like obtain.

  The product of the composition of the present invention (pharmaceuticals, quasi-drugs, veterinary drugs, food / drinks, reagents, devices containing these, etc.) or instructions therefor includes, for example, IL-8 production of activated helper T cells. It is indicated that it is used for the treatment or amelioration of symptoms caused by (preferably neutrophilic inflammation) or that it is used for suppression of IL-8 production of activated helper T cells. It can be

  Here, "indicating the indication on the product or instruction" means that the indication is attached to the main body of the product, the container, the package or the like, or the instruction, the package insert, the advertisement, the other printed matter disclosing the information of the product. It means that the display is attached to etc.

  Hereinafter, the present invention will be more specifically described based on examples, but the present invention is not limited to the following examples.

[Example 1] The effect of tannic acid on dopamine receptors Specifically, the calcium concentration is changed in response to each dopamine receptor (dopamine D1 receptor, dopamine D2 receptor, dopamine D4 receptor, and dopamine D5 receptor) The action of tannic acid on each dopamine receptor was examined by "GPCR Profiler" (registered trademark) service using a cell line to be cultured and an intracellular Ca concentration measurement system using FLIPR (Eurofins). The% agonist activity indicates the degree of maximal response to dopamine, and the% antagonist activity indicates the degree of suppression of dopamine to EC80.

  As a result, tannic acid was found to have an agonist activity for the dopamine D2 receptor and an agonist activity and an antagonist activity for the dopamine D4 receptor and the dopamine D5 receptor (Table 1).

  In addition, determination of RC50 of tannic acid to dopamine D2 receptor was analyzed using a cell line that specifically responds to dopamine D2 receptor stimulation and changes the concentration of cAMP (Discover X). Specifically, it shows the degree when the maximum value at which dopamine suppresses the cAMP increase by forskolin is 100%. The RC50 of tannic acid to the dopamine D2 receptor was 2.23 μM (FIG. 1). The RC50 of dopamine itself is 0.0013 μM.

  From the above, it was suggested that tannic acid is a partial agonist having antagonist activity to dopamine D4 receptor and dopamine D5 receptor. That is, in the absence of dopamine, agonist stimulation is given to the dopamine D4 receptor and the dopamine D5 receptor, but in the presence of dopamine, only dopamine signals via the dopamine D4 receptor and the dopamine D5 receptor are considered to be suppressed. Because of the presence of dopamine produced from immunocompetent cells in the field of physiological immune responses, it is thought that tannic acid relatively enhances the signal through D2R and induces the decrease of intracellular cAMP.

Example 2 Inhibition of IL-8 Production in Activated T Cells by Dopamine D2-Like Receptor Agonist Next, the influence of tannic acid on acquired immune inflammation, particularly neutrophilic inflammation, was analyzed. Plural alloreactive Th1 / Th2 / Th17 cell clones were established, and IFNγ, IL-5, IL-17 and IL-8 produced by them were quantified. The results are shown in FIG. IL-8 production was found to be positively correlated with Th1 cytokine (IFNγ) production and Th17 cytokine (IL-17) production. The correlation values are as follows.

  Correlation between IL-8 and IFNγ (FIG. 2 left): r = 0.3172, P <0.01, correlation between IL-8 and IL-5 (FIG. 2 middle): r = −0.05216, P = ns (Not significant), correlation of IL-8 and IL-17 (FIG. 2 right): r = 0.5485, P = 0.01.

  Stimulation of human PBMC with Candida antigen results in the production of IFNγ, IL-17, and IL-8. Therefore, known dopamine D2-like receptor agonists pramipexole and ropinirole were added to the system, and the IL-8 concentration in the supernatant after 7 days was measured. As a result, suppression of IL-8 production was observed (FIG. 3).

  When a similar experiment was performed with tannic acid, tannic acid suppressed polyclonal IL-8 production of PBMC (FIG. 4). There was no significant difference in IFNγ production.

[Example 3] Effects of dopamine D2-like receptor agonist in neutrophilic airway inflammation model DO11. 10 mice were orally administered each drug (water, pramipexole, ropinirole) three times a week for 6 weeks (0 .3 mg / kg / day). Then, it was sacrificed on the day after ovalbumin (OVA) inhalation was performed continuously for 3 days, BALF (bronchoalveolar lavage fluid) was collected, and the number of neutrophils was counted. As a result, it was found that the dopamine D2-like receptor agonist was effective against the neutrophilic airway inflammation model because it reduced the number of neutrophils (FIG. 5).

[Example 4] Activity of tannic acid related compound to D2 receptor Agonist / antagonist activity of tannic acid related compound, GPCR Biosensor Assay (for tannic acid activity, discovery services of eurofins, other molecules activity) Measurement was conducted using cAMP amount as an index, using Lead discovery service (DiscoverX company's LeadHunter discovery services). Because gallic acid is poorly water soluble, it was dissolved in DMSO and added to the assay system. Table 2 shows the results calculated by standardizing the maximum and minimum responses.

  It should be noted that although the biochemical data of gallic acid show only weak agonist activity, it is thought that this is affected by precipitation in an aqueous solvent due to being dissolved in DMSO and added to the assay system.

Example 5 Effects of Dopamine D2-Like Receptor Agonist in a Psoriasis Model C57BL / 6 mice were mixed with imiquimod (IMQ) cream alone and IMQ cream mixed with a dopamine D2-like receptor agonist (three types) under the mouse ears Applied and observed its thickening. On day 8 from the start, significant ear thickness suppression was observed in the cream administration group containing 10 mg of tannic acid or 10 mg of gallic acid (per 250 mg of cream) compared to IMQ cream alone (FIG. 6).

[Example 6] Effect of dopamine D2-like receptor agonist in ulcerative colitis model (1) Suppressive effect of weight loss 4% dextran sulfate sodium (DSS) containing 0.114 mg / ml ropinirole in C57BL / 6J mice Free water was administered (about 5 ml / day). This dose corresponds to about 28 mg / kg. As a result, significant suppression of weight loss was observed in the ropinirole-administered group compared to the control group on day 4 from the start (FIG. 7A). In addition, when experiments were similarly conducted with 4% dextran sodium sulfate (DSS) containing tannic acid at 10 mg / ml tannic acid, significant suppression of body weight loss was also observed for tannic acid (FIG. 7B).
(2) Intestinal contraction inhibitory effect 4% dextran sodium sulfate (DSS) containing tannic acid at each concentration (1, 5, 10 mg / ml) was administered to C57BL / 6J mice with free water. As a result, significant intestinal contraction suppression was observed in the administration group of 5 or 10 mg / ml tannic acid compared to the control group on the seventh day from the start (FIG. 8).

[Example 7] Effects of a dopamine D2-like receptor agonist of tannic acid in a periodontitis model induced by the immunostimulant carrageenan Rat maxillary left and right second molar tooth side PBS, 1% carrageenan, 1% carrageenan + 1% The work of inserting 2-3 mm of silk yarn soaked in tannic acid was carried out once a week for 3 weeks (n = 4). Four weeks after the start, the degree of alveolar bone resorption was measured by μCT, and 1% carrageenan-induced alveolar bone resorption was significantly suppressed by 1% tannic acid (FIG. 9).

  As described above, the composition of the present invention can be used as a medicine or food or drink for treatment or amelioration of symptoms caused by IL-8 production of activated helper T cells, and also as IL of activated helper T cells. -8 It is possible to use as a reagent for suppressing production.

Claims (4)

  A composition for suppressing IL-8 production of activated helper T cells, which comprises a dopamine D2-like receptor agonist as an active ingredient.   The composition according to claim 1, wherein the dopamine D2-like receptor agonist is tannic acid, gallic acid, catechins or its gallate, ropinirole, or pramipexole.   The composition according to claim 1 or 2, wherein the activated helper T cells are Th1 cells or Th17 cells.   The composition according to any one of claims 1 to 3, which is used for the treatment or amelioration of neutrophilic inflammation.