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WO2018012889A1 - Composition comprenant un inhibiteur d'itac - Google Patents

Composition comprenant un inhibiteur d'itac Download PDF

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Publication number
WO2018012889A1
WO2018012889A1 PCT/KR2017/007484 KR2017007484W WO2018012889A1 WO 2018012889 A1 WO2018012889 A1 WO 2018012889A1 KR 2017007484 W KR2017007484 W KR 2017007484W WO 2018012889 A1 WO2018012889 A1 WO 2018012889A1
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itac
hdac5
vitiligo
migration
expression
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Korean (ko)
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최서연
조은경
빈범호
이태룡
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Amorepacific Corp
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Amorepacific Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids

Definitions

  • composition comprising an inhibitor of ITAC.
  • chemokines One important role of chemokines is to mediate immune responses and tumorigenesis through induction of cell migration. Some chemokines are involved in mouse vitiligo. Interferon-inducible T-cell alpha chemoattractant (ITAC) has a high binding affinity for CXCR3 compared to other ligands to elicit a strong chemotactic response from immune cells. The effect of ITAC on melanocyte migration and pigmentation and its relationship to related disorders is unknown. Class II histone deacetylases (HDACs), particularly HDAC5, deacetylate p53 proteins involved in various cellular processes, including cell migration, and regulate protein stability and activity.
  • ITAC Interferon-inducible T-cell alpha chemoattractant
  • HDACs Class II histone deacetylases
  • HDACs deacetylate p53 proteins involved in various cellular processes, including cell migration, and regulate protein stability and activity.
  • the present study investigated the role of ITAC in pathological conditions such as vitiligo and in vitro evidence for the migratory and hypopigmentation effects of ITAC on melanocytes by deacetylation of p53 via HDAC5. Provides a review on the translation side.
  • the present invention provides a composition for the prevention or treatment of vitiligo or vitiligo metastasis comprising an interferon-inducible T-cell alpha chemoattractant (ITAC) inhibitor.
  • ITAC interferon-inducible T-cell alpha chemoattractant
  • the present invention provides a composition for vitiligo or detection comprising a reagent for detecting the gene expression amount of ITAC.
  • the present invention provides a method for screening a prophylactic or therapeutic agent for vitiligo comprising identifying whether it inhibits the expression of one or more genes of ITAC, CXCR3 and CXCR7.
  • the present study investigated the role of ITAC in pathological conditions such as vitiligo and in vitro evidence for the migratory and hypopigmentation effects of ITAC on melanocytes by deacetylation of p53 via HDAC5. Provides a review on the translation side.
  • Figure 1a shows the results of comparing the migration of human epidermal melanocytes (NHEM) according to ITAC, MIG and IP-10 treatment.
  • Figure 1b shows the NHEM migration results according to the change in ITAC concentration.
  • 1C shows Western blot results of CXCR3 and CXCR7 protein expression levels.
  • 1D shows the results of migration analysis of NHEMs in the presence of ITAC after CXCR3 or CXCR7 neutralizing antibody treatment.
  • 2A shows the results of analyzing biological processes that are significantly up- or down-regulated by ITAC treatment.
  • 2C shows HDAC9 mRNA levels following ITAC treatment.
  • Figure 3a shows the results confirmed the cell migration according to HDAC5 and HDAC9 knockdown in NHEM.
  • Figure 3b shows the results confirmed the cell migration following HDAC5 overexpression.
  • Figure 3c shows the results of confirming the HDAC5 protein level following ITAC treatment.
  • 4A shows the results of confirming the levels of total p53 and acetylated p53 in NHEM following ITAC treatment.
  • Figure 4b shows the results of confirming the level of total p53 and acetylated p53 following HDAC5 overexpression.
  • Figure 4c shows the results of confirming the levels of total p53 and acetylated p53 according to HDAC5 knockdown.
  • FIG. 5A shows the results confirming the effects on cell migration in the absence or absence of ITAC when HDAC5 overexpression (HDAC5-myc), p53 overexpression (p53-Flag) or both are overexpressed (HDAC5-Myc + p53-Flag). Indicates.
  • Figure 5b shows the results confirming the effect on MMP1 expression following ITAC treatment.
  • Figure 6a shows the results of confirming the change in melanin amount according to the ITAC treatment.
  • Figure 6b shows the results of confirming the melanin amount, total p53 or acetylated p53 protein level after ITAC treatment after UV irradiation.
  • Figure 6c shows the result of confirming the amount of melanin according to HDAC5 overexpression.
  • FIG. 7 shows the results of staining skin samples (# 1 and # 2) of normal (N) or hypopigmented lesions (L) with anti-ITAC antibodies (green) and anti-HMB45 (red).
  • the nucleus is represented by DAPI (blue), arrow indicates melanin and triangle indicates melanin forming cells.
  • DAPI, anti-ITAC antibody and anti-HMB45 stained portions in black and white drawings are represented in white.
  • Figure 9a is a result confirming the cell migration effect of ITAC in human melanoma cell line (WM266-4).
  • Figure 9b is the result confirming the cell migration effect of ITAC in human melanoma cell line (SK-MEL-28).
  • Figure 9c is a result confirming the cell migration effect of ITAC in human melanoma cell line (MNT-1).
  • 9D shows the results of detecting ITAC, CXCR3, and CXCR7 in melanocytes and melanoma cells.
  • Figure 10a is a mRNA expression result confirming the knockdown of HDAC5 by siRNA treatment.
  • 10b is a mRNA expression result confirming the knockdown of HDAC9 by siRNA treatment.
  • Figure 11a is a result confirming that acetylation of alpha-tubulin is affected by ITAC treatment in NHEM.
  • 11A shows the results confirming that acetylation of alpha-tubulin is affected by HDAC5 deletion in NHEM.
  • Figure 11c is a result confirming the changes in p53 and TYR expression according to ITAC treatment in melanoma cells.
  • Figure 12a is a result confirming the effect on TYR expression in NHEM following ITAC treatment.
  • Figure 12b is a result confirming the effect on MITF expression in NHEM following ITAC treatment.
  • Figure 12c is a result confirming the effect on TRP1 expression in NHEM following ITAC treatment.
  • Figure 12d is a result confirming the effect on the expression of DCT in NHEM by ITAC treatment.
  • Figure 13a is the result confirming the effect on TYR expression according to ITAC treatment in the case of p53 knockdown.
  • Figure 13b is the result confirming the effect on MITF expression according to ITAC treatment in the case of p53 knockdown.
  • Figure 13c is the result confirming the effect on TRP1 expression according to ITAC treatment in the case of p53 knockdown.
  • Figure 13d is the result confirming the effect on DCT expression according to ITAC treatment in the case of p53 knockdown.
  • neutralizing means reducing the activity in the presence of an inhibitor, as compared to the activity in the absence of the substance.
  • the decrease in activity can be, for example, about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more.
  • One embodiment of the present invention relates to a composition for the prevention or treatment of vitiligo or vitiligo metastasis comprising an interferon-inducible T-cell alpha chemoattractant (ITAC) inhibitor.
  • ITAC interferon-inducible T-cell alpha chemoattractant
  • composition according to the embodiments can effectively inhibit melanocyte-like cell migration, contribute to the prevention, treatment or improvement of their symptoms of vitiligo or vitiligo metastasis.
  • the ITAC inhibitor may be a substance that inhibits the expression or activity of the ITAC gene or the action or activity of the ITAC.
  • the ITAC inhibitor may be an oligonucleotide that binds at least a portion of the ITAC mRNA or a neutralizing antibody of the ITAC.
  • the oligonucleotide may be any one or more of? SiRNA, shRNA, and miRNA.
  • the gene expression or activity inhibitor may be any one or more of the siRNA, shRNA and miRNA that induces RNA interference (RNAi) phenomenon.
  • RNAi phenomenon of inducing interference of the gene mRNA may be used to suppress the mRNA expression of the gene.
  • miRNA is a kind of endogenous small RNA existing in cells and is derived from hairpin-shaped transcripts derived from DNA which does not synthesize proteins. miRNA binds to the complementary sequence of the 3'-UTR of the target mRNA and induces translation inhibition or destabilization of the mRNA, ultimately acting as a repressor to inhibit protein synthesis of the target mRNA .
  • One miRNA targets several mRNAs, and mRNAs are known to be regulated by multiple miRNAs.
  • Other RNA inducing RNAi phenomenon is short interfering RNA (siRNA), which is short RNA of about 19 to 27 mer, and shRNA having a short hairpin structure.
  • the oligonucleotide is double stranded and can be any one of siRNA, shRNA and miRNA.
  • the ITAC inhibitor may be an anti-ITAC antibody.
  • the ITAC inhibitor may be a substance that inhibits the expression or activity of the ITAC receptor.
  • the ITAC receptor may be CXC-chemokine receptor type 3 (CXCR3), CXC- chemokine receptor type 7 (CXCR7) or a mixture thereof.
  • Substances that inhibit the expression or activity of the ITAC receptor may be oligonucleotides that bind to at least a portion of the ITAC receptor mRNA or neutralizing antibodies of the ITAC receptor.
  • the oligonucleotide may be any one or more of? SiRNA, shRNA, and miRNA. Since the siRNA, shRNA and miRNA are as described above, description thereof is omitted.
  • the ITAC inhibitor may be an anti-CXCR3 antibody, an anti-CXCR7 antibody or a mixture thereof.
  • the ITAC inhibitor may be a substance that inhibits HDAC: histone deacetylase-5 (HDAC5), a downstream effector of ITAC.
  • HDAC5 histone deacetylase-5
  • the substance that inhibits HDAC5 may be, for example, a substance that inhibits HDAC5 expression or activity.
  • the substance that inhibits the expression or activity of HDAC5 may be, for example, an oligonucleotide that binds to at least a portion of HDAC5 mRNA or a neutralizing antibody of HDAC5.
  • the oligonucleotide may be any one or more of? SiRNA, shRNA, and miRNA. Since the siRNA, shRNA and miRNA are as described above, description thereof is omitted.
  • the neutralizing antibody of HDAC5 may be an anti-HDAC5 antibody.
  • the mRNA sequence of the ITAC may be represented by NM_005409, NM_001302123, or SEQ ID NO: 1.
  • the mRNA sequence of CXCR3 can be represented by NM_001142797, NM_001504 or SEQ ID NO: 2.
  • the mRNA sequence of CXCR7 can be represented by NM_001047841, NM_020311, or SEQ ID NO: 3.
  • the sequence of HDAC5 mRNA may be represented by NP_001015053, NM_005474, NM_139205, or SEQ ID NO: 4.
  • compositions according to embodiments of the present invention may be provided in various forms of food additives or functional food.
  • it may be processed into fermented milk, cheese, yoghurt, juice, probiotic and health food, and may be used in the form of various other food additives.
  • the composition according to the embodiments of the present invention may be a composition for health food.
  • the health food composition inhibits the action of ITAC, inhibits melanocyte-forming cells, and exhibits a low pigmentation effect.
  • the health food composition may relieve or improve the symptoms or metastasis of vitiligo, vitiligo by inhibiting the action of ITAC.
  • the health food composition may be formulated as pills, capsules, tablets, granules, caramels or drinks. In other embodiments, it may be processed in the form of a liquid, powder, granules, tablets or tea bags and the like.
  • composition may be administered by various methods, such as simple drinking, injection, spray or squeeze.
  • the composition may contain other ingredients and the like that can give a synergistic effect to the main effect within a range that does not impair the main effect of the present invention.
  • it may further include additives such as perfumes, pigments, fungicides, antioxidants, preservatives, moisturizers, thickeners, inorganic salts, emulsifiers and synthetic polymer materials to improve physical properties.
  • additives such as perfumes, pigments, fungicides, antioxidants, preservatives, moisturizers, thickeners, inorganic salts, emulsifiers and synthetic polymer materials to improve physical properties.
  • supplementary ingredients such as water soluble vitamins, oil soluble vitamins, polymer peptides, polymer polysaccharides and seaweed extract may be further included.
  • ingredients may be suitably selected and formulated by those skilled in the art according to the dosage form or purpose of use, and the amount thereof may be selected within a range that does not impair the object and effect of the present invention.
  • the addition amount of the components may be 0.01% to 5% by weight, for example 0.01% to 3% by weight based on the total weight of the composition.
  • composition according to the embodiments of the present invention may be a pharmaceutical composition.
  • the pharmaceutical composition may inhibit the action of ITAC to inhibit melanocyte-like cell migration, exhibit a hypopigmentation effect, and prevent, treat or alleviate the symptoms or metastasis of vitiligo or vitiligo.
  • the pharmaceutical composition may be formulated in oral or parenteral dosage forms in various forms, such as solid, semi-solid or liquid, further comprising a commercially available inorganic or inorganic carrier in accordance with conventional methods.
  • the oral dosage form can be, for example, tablets, pills, granules, soft / light capsules, powders, granules, powders, emulsions, syrups, pellets, and the like.
  • Parenteral dosage forms are, for example, injections, drops, and the like.
  • the pharmaceutical composition may further contain preservatives, stabilizers, hydrating or emulsifying accelerators, pharmaceutical auxiliaries such as salts or buffers for controlling osmotic pressure and other therapeutically useful substances.
  • the pharmaceutical composition may be administered orally, parenteral, topical, transdermal, subcutaneous, rectal, intravenous, intramuscular, intraperitoneal, and the like.
  • the actual dosage of the active ingredient should be determined in light of several relevant factors such as the severity of the symptom, the route of administration chosen, the age, sex, weight and health of the subject. Generally, the dosage of the active ingredient is 0.001 mg / kg / day to 2000 mg / kg / day, for example 0.5 mg / kg / day to 1500 mg / kg / day.
  • an embodiment of the present invention may provide a composition for detecting vitiligo including a reagent for detecting an ITAC gene expression amount.
  • the reagent for detecting the expression of the ITAC gene may be one capable of measuring the level of a transcript of the ITAC gene.
  • the detection reagent may be a primer pair or probe that specifically binds to an ITAC transcript.
  • the amount of ITAC expression is increased by the composition compared to the normal group, it can be determined that there is a vitiligo or vitiligo metastasis.
  • the primer is complementary to the gene mRNA and may include, but is not limited to, a primer pair capable of amplifying the mRNA.
  • the probe comprises a polynucleotide consisting of the sequence of the gene mRNA; And polynucleotides including 10 or more consecutive nucleotides as fragments of the polynucleotides, but are not limited thereto.
  • the expression level assay of the gene was polymerase chain reaction (PCR), reverse transcriptase polymerase chain reaction (RT-PCR), northern blot analysis, western blot analysis, and dot blot.
  • PCR polymerase chain reaction
  • RT-PCR reverse transcriptase polymerase chain reaction
  • ELISA enzyme-linked immunosorbent assay
  • microarrays such as the TaqManTM probe probe using allele-specific hybridization, allele specific hybridization through polymerization Probe method using -specific hybridization, restriction fragment length polymorphism (RFLP) method using restriction enzyme, dynamic allele-specific hybridization using melting temperature (Tm, melting temperature) Hybridization, pyrosequencing using polymerization, microarray using allele-specific extension, etc. But it is not limited to this.
  • the sample may be epithelial cells, keratinocytes, melanocytes, mast cells, or fibroblasts isolated from humans, for example For example, it may be a keratinocyte.
  • Obtaining a sample from a subject may be performed according to a conventional method in the art, and may be performed by a non-invasive method without causing irritation to the skin, such as tape stripping to the skin, but is not limited thereto.
  • the tape stripping may be performed, for example, 1-20 times, for example 5 times, and a sample may be obtained without causing skin irritation within the above range.
  • Assaying the expression level of the gene may comprise measuring the level of a transcript of the gene or a protein expressed therefrom in the sample.
  • the level of transcript of a gene can be measured by measuring the amount of transcript hybridized with at least one of the primer pair and probe in the sample.
  • the expressed protein level can be measured by measuring the amount of protein hybridized with the antibody in the sample.
  • one or more of a primer pair or probe specifically binding to a transcript of one or more genes of ITAC, CXCR3 and CXCR7, an antibody specifically binding to a protein expressed from the one or more genes may provide a kit for diagnosing vitiligo.
  • an embodiment of the present invention may provide a method of diagnosing vitiligo or vitiligo through ITAC expression.
  • the method detects the amount of ITAC expression in the sample and can be diagnosed as vitiligo when the ITAC is overexpressed compared to normal.
  • the sample may be an epidermal tissue to be diagnosed.
  • the sample may be one or more of immune cells, such as epithelial cells, keratinocytes, melanocytes, mast cells, etc., isolated from a diagnosis subject.
  • the overexpression is more than 1.1 times, more than 1.2 times, more than 1.3 times, more than 1.4 times, more than 1.5 times, more than 1.6 times, more than 1.7 times, more than 1.8 times, more than 1.9 times the amount of gene expression compared to normal expression.
  • the method may further comprise measuring the expression of the ITAC receptor CXCR3 or CXCR7, or both, in addition to ITAC expression.
  • ITAC expression overexpression of CXCR3 or CXCR7 can diagnose vitiligo or vitiligo metastases.
  • the overexpression is more than 1.1 times, more than 1.2 times, more than 1.3 times, more than 1.4 times, more than 1.5 times, more than 1.6 times, more than 1.7 times, more than 1.8 times, more than 1.9 times the amount of gene expression compared to normal expression.
  • a method for screening a prophylactic or therapeutic substance for vitiligo may be provided.
  • the method for screening for or preventing vitiligo is to treat a test substance in human epidermal tissue and determine whether the test substance inhibits the expression of one or more genes of ITAC, CXCR3 and CXCR7 in human epidermal tissue. It may include.
  • the epidermal tissue may be one or more of immune cells, such as epithelial cells, keratinocytes, melanocytes, mast cells, etc., isolated from a diagnosis subject.
  • immune cells such as epithelial cells, keratinocytes, melanocytes, mast cells, etc.
  • the determination as the prophylactic or therapeutic substance may be determined as a prophylactic or therapeutic substance when the expression of the expression of the untreated group is significantly suppressed.
  • inhibition of expression may be a P ⁇ 0.05 reduction in expression for untreated groups.
  • ITAC HDAC5 Through p53 Deacetylation Through melanocyte-forming and Low pigmentation Induces: Possible Role of ITAC in Pigment-Related Disorders
  • chemokines One important role of chemokines is to mediate immune responses and tumorigenesis through induction of cell migration.
  • chemokines are involved in mouse vitiligo.
  • Interferon-inducible T-cell alpha chemoattractant has a high binding affinity for CXCR3 compared to other ligands to elicit a strong chemotactic response from immune cells.
  • HDACs Class II histone deacetylases
  • HDAC5 deacetylate p53 proteins involved in various cellular processes, including cell migration and regulate protein stability and activity.
  • ITAC expression is increased in the epidermis of vitiligo skin.
  • HDAC5 deacetylates and destabilizes its substrate, p53, to participate in ITAC-mediated cellular processes.
  • CXCR3 CXC-chemokine receptor type 3
  • HDAC histone deacetylase
  • IP-10 interferon-gamma-induced protein 10
  • ITAC interferon-inducible T-cell alpha chemoattractant (ITAC)
  • MIG monookine induced by interferon-gamma
  • MMP1 matrix metallopeptidase 1
  • NHEM normal human epidermal melanocytes
  • TYR tyrosinase
  • MITF microphthalmia-associated transcription factor
  • TRP1 tyrosinase-related protein-1
  • DCT dopachrome tautomerase
  • HMB45 human melanoma black-45
  • ITAC chemokine: induces migration of melanocytes, melanoma and immune cells
  • inhibiting ITAC and its receptors contributes to the improvement of melanoma and vitiligo.
  • compositions for the management / treatment of certain skin diseases using neutralizing antibodies of ITAC and ITAC receptors are provided.
  • chemokines to promote the migration of melanocytes
  • T-cell alpha chemoattractant elicits a strong chemotactic response from immune cells.
  • ITAC treatment up-regulated histone deacetylase 5 (HDAC5) and down-regulated p53, a known target of HDAC5. Knockdown or overexpression of HDAC5 and p53 confirmed that HDAC5 mediates ITAC-induced migration by decreasing p53 levels through deacetylation. ITAC treatment can also reduce pigmentation with p53- and HDAC5-dependency. Finally, increased migration of human melanoma cells by ITAC treatment and increased ITAC expression in the epidermis of vitiligo skin were identified.
  • Keyword hdac5, p53, itac, melanocytes, migration, melanoma, vitiligo
  • Lysine (lysine) acetylated suggest that grows a key regulator of the deformed first, acetylation / deacetylation upset physiologically active protein after transfer that can affect more than 1750 proteins in human cells.
  • Histoneacetyltransferases transfer acetyl moieties from acetyl coenzyme A to ⁇ -amines of lysine residues to catalyze lysine acetylation on histone proteins, histone deacetylases. (HDAC) catalyzes the opposite process.
  • HDAC Unlike histone acetyltransferases with opposite structure and function, HDAC is classified into four distinct classes based on sequence homology to the yeast counterpart: Class I (HDAC1, 2, 3) , And 8), Class II (IIa: HDAC4, 5, 7, 9, and MITR; IIb: HDAC6 and 10), Class III (SIRT1-7), and Class IV (HDAC11).
  • Class I HDACs are essentially expressed in the nucleus and found in all tissues, and Class II HDACs exhibit tissue specific expression patterns and involve nucleocytoplasmic shuttling, which is responsible for deacetylation of non-histone proteins. It suggests that you are involved.
  • p53 a transcription factor that functions in cell growth arrest, apoptosis, and senescence
  • HDAC5 acts p53dp by deacetylating lysine 120 (K120).
  • HDAC HDAC and its targets have been studied relatively well, the factors that activate particular HDACs are less understood. Because HDAC participates in various cellular processes, its dysregulation is associated with the development of cancer and inflammatory diseases. Although HDAC inhibitors have been studied in clinical trials for the treatment of these diseases, the molecular basis for HDAC inhibition in patients is not fully known. 6 HDAC has been shown to be important for the motility of various cells and tumors through deacetylation of motility related proteins such as alpha-tubulin and cortactin. 7-8 The discovery and potential role in HDAC metastasis and inflammation suggest a relationship between HDAC and disease processes involved in cell migration.
  • CXC-chemokine receptor type 3 CXCR3
  • MIG monocaine
  • IP-10 interferon-g inducing protein
  • ITAC interferon-induced T-cells
  • IP-10 and ITAC are expressed in basal keratinocytes, but MIG is expressed in dermal infiltrate, and ITAC is expressed in IPX in CXCR3. Binds with higher affinity than 10 or MIG.
  • HDAC5 a Class IIa HDAC
  • ITAC treatment reduced pigmentation in a p53- and HDAC5-dependent manner and increased ITAC expression in the epidermis of vitiligo skin.
  • NHEM derived from intermediate pigmented skin (Cascade Biologics, Portland, OR) and containing 5% CO 2 in medium 254 supplemented with human melanocyte growth aid (HMGS; Life Technologies, Carlsbad, Calif.) Incubation was in a wet incubator. NHEMs were treated with the indicated chemokines of varying concentrations (Table S1; R & D R & D system, Minneapolis, MN).
  • Transfer assays were performed in a Boyden chamber after treatment indicated on the cells according to published method 10 .
  • NHEMs were pretreated with 50 ⁇ g / ml of neutralizing antibody against CXCR3 (R & D system), CXCR7 (Biolegend, San Diego, Calif.), Or each isotype-matched control antibody.
  • Specific protocols for the Boyden chamber assay are provided in the supplementary information.
  • NHEM was treated with 50 ng / ml of ITAC for 48 hours and total RNA was isolated using TRIzol reagent (Gibco-BRL, Gaithersburg, MD). 15 ng of total RNA was used for analysis. Microarray analysis methods are described in detail in Supplementary Information.
  • RNA 2 ⁇ g was used for cDNA synthesis using random hexamers and reverse transcriptase (Promega, Madison, Wis.) According to the manufacturer's instructions. Specific protocols are given in the supplementary information.
  • Cells were treated with ITAC 50 or 200 ng / ml for 4 days or transfected with various concentrations of HDAC5-Myc expressing plasmids for 2 days. Specific methods of cell elution and melanin assays are provided in the supplemental information.
  • Dermal cells such as macrophages, Langerhans cells, gamma delta-T cells, mast cells, keratinocytes and melanocytes produce various chemokines (Table 1, Supplemental Information). Reference).
  • chemokines One important role of chemokines is to mediate cell migration.
  • NHEM skin-derived chemokines to induce migration of normal human epidermal melanocytes (NHEM) using a chamber assay.
  • NHEMs migrate to FK506, a known inducer of melanogenesis cell migration, and SDF1, which appears to induce NHEM migration (see FIG. 8, Supplemental Information).
  • chemokines such as 10 CTACK, PARC, ITAC, RANTES, TARC and Lptn
  • ITAC a CXCR3-targeting chemokine involved in recruiting immune subtypes of other subtypes to the site of inflammation, since only ITAC, not MIG and IP-10, induced NHEM migration ( Figure 8, Figures 1a, b). ).
  • ITAC the migration effect of ITAC was confirmed in three different human melanoma cell lines, and the migration of these cells was significantly increased (FIG. 9).
  • ITAC will play a distinct role in melanogenesis, i.e. by regulating melanocyte-like cell migration.
  • ITAC-induced NHEM mechanism we first assessed the levels of the ITAC receptors CXCR3 and CXCR7 16 , which initiate ITAC-related signals using specific antibodies, and confirmed that both proteins were expressed in NHEM. (FIG. 1C).
  • transfer assays After removal of endogenous CXCR3 or CXCR7 using specific neutralizing antibodies. ITAC-induced migration was significantly reduced after treatment of each of the two neutralizing antibodies as compared to each isotype control (FIG.
  • ITAC up-regulates mRNA expression of migration-related genes in NHEMs.
  • HDAC5 and HDAC9 which, as Class IIa members, were able to regulate protein activity by deacetylating non-histone proteins and suggested to be involved in cell-motility.
  • ITAC treatment in RT-qPCT analysis Figure 2b, c.
  • HDAC5 mediates ITAC-induced migration of NHEMs.
  • siRNAs specific for HDAC5 and HDAC9 were knocked down HDAC5 and HDAC9 and chamber assays performed in the presence or absence of ITAC were performed. Each gene knockdown was confirmed by measuring mRNA expression levels by RT-qPCT (FIG. 10). NHEMs responded to FK506 with about a 2-fold increase in migration as expected (FIG. 3A, lane 2). Compared with scrambled siRNA control that induced NHEM migration without ITAC (lane 3), HDAC5 knockdown reduced migration but HDAC9 knockdown had no effect (lanes 4 and 5). In the presence of ITAC, only HDAC5 significantly inhibited migration compared to the scrambled control (lane 6 vs.
  • ITAC treatment migration of control cells was markedly increased to a level comparable to that of HDAC5 overexpression, and HDAC5 overexpressing cells showed an additive migration effect (FIG. 3b, the last two lanes).
  • HDAC5 protein levels increased with upregulation of HDAC5 mRNA after ITAC treatment (FIG. 3C).
  • HDAC5 affects the p53 acetylation status in ITAC-treated NHEMs.
  • HDAC5 The downstream target of HDAC5 was identified in ITAC-induced migration.
  • alpha-tubulin which is deacetylated by HDAC5 in neurons as a migration-related protein. 7
  • the acetylation status of alpha-tubulin was not affected by ITAC treatment (FIG. 11A) or HDAC5 deletion in NHEM (FIG. 11B), indicating that alpha-tubulin induced HDAC5 in ITAC-induced melanogenesis cell migration. Imply that it is not a target.
  • p53 plays a role in cell migration.
  • 17 p53 is an HDAC5-interacting protein that has been shown to overexpress HDAC5 in cells by immunoaffinity isolation, 18 HDAC5 directly deacetylates p120 K120, resulting in a 5 MDM2-dependent analog Leads to quitylation and degradation pathways. Therefore, it was examined whether acetylated p53 or total p53 levels were affected when HDAC5 mRNA and protein levels were increased by ITAC treatment (FIGS. 2B, 3C). In ITAC treated NHEMs, the amount of acetylated p53 revealed by the antibody recognizing at least two acetylated lysine residues 373 and 382 of p53 showed a slight decrease in total p53 (FIG. 4A).
  • HDAC5 was overexpressed or knocked down to examine the effect of HDAC5 on p53 expression levels. HDAC5 overexpression corresponded to decreases in acetylated p53 and total p53 levels (FIG. 4B) and both p53 increased when HDAC5 knocked down to siRNA (FIG. 4C). This data suggests that the acetylation status of p53 is regulated by HDAC5 and that downregulation of p53 is involved in ITAC-induced cell activity.
  • p53 overexpression inhibits ITAC-induced and HDAC5-mediated NHEM migration.
  • HDAC5 dependently overexpressed HDAC5, p53, or both were performed Bodenchamber assay to determine whether p53 affects NHEM migration.
  • HDAC5 overexpression in the absence of ITAC significantly increased cell migration (FIG. 5a, lane 2), but this effect was lost by p53 overexpression (lane 4), suggesting an involvement of p53 in HDAC5-induced cell migration ( Lane 5 vs. 7).
  • HDAC5 overexpression in ITAC treated cells increased cell migration more compared to mock-treated controls (lane 5 vs. 6) and this effect was reduced by p53 overexpression (lane 6 vs. 8). ).
  • p53 is a downstream effector of HDAC5 and is involved in ITAC- and HDAC5-induced cell migration.
  • P53 transcription targets also known to be negatively regulated by p53, migration-related gene matrix metallopeptidase 1 (MMP1) 20 and collagen 21 Reversed upregulation by ITAC treatment as measured by microarray analysis of MMP1 (Table 2) and RT-qPCR (FIG. 5B), indicating that the transcriptional activity of p53 is reduced in ITAC-treated cells.
  • MMP1 migration-related gene matrix metallopeptidase 1
  • ITAC treatment results in low pigmentation of NHEM through p53 downregulation.
  • CXCR3 ligands such as IP-10 and MIG
  • CXCR3 ligands are upregulated at delayed pigmented sites.
  • the amount of TYR protein decreased markedly with decreasing p53 expression level (FIG. 11C).
  • ITAC is the melanogenesis-related gene TYR, tyrosinase-related protein-1.
  • DCT mRNA expression levels were reduced (FIG. 12).
  • ITAC causes an anti-melanogenic effect in p53-associated pigmentation
  • ITAC overproduction may be related to hypopigmentation disorders because of its migration to immune and melanogenic cells.
  • Vitiligo is a common type of immune-associated hypopigmentation disorder.
  • ITAC expression changes in vitiligo lesions through immunohistochemical analysis using anti-ITAC antibodies.
  • melanin (arrows) and melanocytes (triangles) were observed along the epidermal basement membrane only in normal skin (FIG. 7, N # 1).
  • ITAC expression in vitiligo lesion epidermis was significantly upregulated and abundant compared to normal skin where little ITAC was found (Figure 7, L # 1, L # 2, vs N # 1).
  • HDAC5 and HDAC9 levels increased in ITAC treated cells compared to untreated controls. Only HDAC5 of these genes was involved in ITAC-induced NHEM migration (FIG. 3A). Based on previous reports, 7 we first tested alpha-tubulin as a target of HDAC5 to account for the shifting effects of ITAC. ITAC treatment and siRNA knockdown of HDAC5 were not associated with changes in acetylated alpha-tubulin levels (FIG. 11A, B), suggesting that other targets are involved in ITAC-induced melanogenesis.
  • p53 is an important regulatory protein in a variety of signal pathways, including DNA damage response 25 and migration of various cell types, including tumor cells, 26 fibroblasts, 27 and keratinocytes 28 .
  • HDAC1 The activity and stability of p53 is highly dependent on its acetylation state, which is antagonized by certain HDAC protein complexes, including HDAC1 or SIRT1.
  • HDAC1 is primarily present in the nucleus, while other HDACs can regulate p53 acetylation in the cytoplasm. 4
  • HDAC5 regulates p53 acetylation at K120. Based on the hypothesis that 5 p53 is deacetylated by HDAC5 in ITAC-induced melanogenesis cell migration, HDAC5 reduces acetylated p53 protein and total p53 protein (FIG. 4b, c), thereby reducing melanogenesis cell migration. Mediation (FIG. 5A).
  • ITAC treatment was observed to induce hypopigmentation of normal and UV-treated melanocytes ( Figures 6a, b).
  • ITAC treatment down-regulated melanogenesis-related gene expression and p53 protein levels (FIG. 2; FIG. 4A, FIG. 6B).
  • p53 was up-regulated by UV exposure and induced melanogenesis by increasing TYR and TRP1 expression. 22-23 p53 was found to be involved in ITAC-induced hypopigmentation (FIG. 6B). Since HDAC5 is the primary regulator of p53 stability through deacetylation in ITAC-induced melanogenesis, and HDAC5 overexpression is associated with depigmentation (FIG.
  • HDAC5 is p53 deacetylated, resulting in melanogenesis- Relevant genes may be directly involved in ITAC-induced hypopigmentation through down-regulation. Genes affected by p53 down-regulation may be the cause of melanogenesis cell migration, hypopigmentation or both after ITAC treatment. Collagens and MMP1, cell migration-related genes negatively regulated by p53, were found to be up-regulated in ITAC-treated cells (FIG. 5B; Table 2). These up-regulated genes may also be involved in ITAC-induced hypopigmentation. These data also suggest that destabilization of p53 via deacetylation via Class IIa HDAC, especially HDAC5, plays an important role in ITAC-induced cellular processes such as migration and hypopigmentation.
  • Acute and chronic dermatitis can cause hypopigmentation or hyperpigmentation, depending on the interaction between environmental and genetic factors.
  • MIG and IP-10 are up-regulated at delayed pigmented sites in which inflammatory cells are depressed, resulting in melanocyte activity and chronic melanin synthesis.
  • ITAC is upregulated in the epidermis of low pigmented disease vitiligo skin (FIG. 7), and IP-10 is not deregulated when compared to healthy controls, 30 which is a different function between CXCR3 ligands and humans of ITAC. It suggests potential involvement in the development of vitiligo.
  • MIG and IP-10 are important in mouse vitiligo and that ITAC does not play a major role. 31 These differences are due to epidermal structural differences between mice and humans, for example: 1) the human epidermis is made up of multiple layers, creating a different environment than the thin epidermis of the mouse; Although present in all, mouse melanocytes are present only in the vesicle area. ITAC secreted from keratinocytes on the basement membrane will directly affect melanocytes in the intervesicle region where no melanocytes are present in the mouse.
  • MIG and IP-10 had no effect on pigmentation or melanogenesis at high concentrations, suggesting that they would not directly affect melanocytes and would play a different role than ITAC.
  • MIG, IP-10, and ITAC are closely related interferon-g-reactive chemokines and mediate signals for attracting T lymphocytes through CXCR3, their effects on melanocyte migration and melanogenesis are influenced by cellular context. Depends on This finding is explained in part by their different binding affinity for CXCR3, different ITAC co-receptors on melanocytes such as CXCR7, and their different expression levels in pathological conditions.
  • HDAC5 keratinocytes on the basement membrane around lesion spots and by skin cells in various types of inflammatory skin diseases, 12 its downstream effectors, HDAC5 and p53, act on mature melanocytes. This may be important to control.
  • Several pigmentation-related disorders such as solar lentigo, melasma, and melanoma are represented by and exacerbated by melanocyte condensation. This study highlights the possibility that p53 down-regulation via HDAC5 stimulation is one of the strategies to mitigate these disorders by inducing migration of condensed melanocytes and simultaneously inducing hypopigmentation.
  • Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett 1997; 420 : 25-7.
  • NHEM normal human neonatal epidermal melanocytes
  • NHEMs were treated for 48 hours with 50 ng / ml ITAC and microarray analysis was performed using 50ng total RNA.
  • Biological processes significantly up- or down-regulated by ITAC treatment were grouped using gene ontology analysis (GO) analysis via DAVID.
  • BH P value Benjamini-Hochberg multiple test-corrected p value.
  • HDAC5 b
  • HDAC9 c
  • HDAC5 mediates ITAC-induction in NHEMs.
  • siRNA was transfected in NHEM for 48 hours. Cells were allowed to migrate for 24 hours in the absence or presence of 50 ng / ml ITAC after transfection and fixed for counting. Scrambled siRNA and FK506 were used as negative and positive controls, respectively. The data represent three independent experiments (* P ⁇ 0.05, *** P ⁇ 0.001).
  • HDAC5-Myc plasmid was introduced into NHEM for 48 hours. Cells were allowed to migrate for 24 hours in the absence or presence of 50ng / ml ITAC. The migrated cells were counted. The data represent three independent experiments (* P ⁇ 0.05, *** P ⁇ 0.001).
  • HDAC5 protein expression levels were measured by Western blot after 48 hours of 50 ng / ml ITAC treatment. Western blot analysis was performed repeatedly and representative images are shown. Relative band intensity.
  • HDAC5 affects the p53 acetylation status in ITAC-treated NHEMs.
  • NHEMs were treated with 50 ng / ml ITAC for 48 hours.
  • the levels of acetylated p53 protein and total p53 protein were measured by Western blot with the indicated antibodies.
  • HDAC5-Myc overexpression construct (b) or siRNA for HDAC5 (c) were transfected into NHEM for 48 hours. Mock siRNA and scrambled siRNA were used as controls for HDAC5-Myc and HDAC5-specific siRNA, respectively.
  • the levels of acetylated p53 protein and total p53 protein were measured by Western blot with the indicated antibodies.
  • GAPDH was used as loading control.
  • Western blot analysis was performed repeatedly and representative images are shown. Relative band intensity.
  • p53 overexpression inhibits ITAC-induced and HDAC5-mediated NHEM migration.
  • NHEMs were transfected with mock-transfection (lanes 1, 5), or HDAC5-Myc expressing plasmids (lanes 2, 6), p53-flag (lanes 3, 7) or both (lanes 4, 8). Specified. 48 hours after transfection were allowed to migrate for 24 hours in the absence or presence of 50ng / ml ITAC and fixed for counting. Data is representative of three independent experiments (* P ⁇ 0.05).
  • mRNA levels of MMP1 in NHEM were measured before and after ITAC treatment with RT-qPCT. The value was normalized to GAPDH. The data represent three independent experiments (* P ⁇ 0.05).
  • ITAC is abundant in the epidermis of vitiligo skin.
  • Skin samples (# 1 and # 2) of normal (N) or hypopigmented lesions (L) from two patients with vitiligo were stained with anti-ITAC antibody (green) and anti-HMB45 (red) and the nucleus was DAPI. Stained (blue). Bright field images were taken to visualize melanin in the tissues (arrows). Triangles represent melanocytes. HMB45, human melanoma black-45. Scale bar 50 ⁇ m.
  • Human melanoma MNT-1 cell line was provided by Dr. Lee Ae-young of Dongguk University who received the cell line from Dr. Vincent J. Hearing of National Institutes of Health, Bethesda, Maryland, USA. Cells were incubated at 37 ° C. in DMEM (Lonza, Basel, Switzerland) containing 20% FBS and antibodies.
  • WM266-4 human melanoma cell line was obtained from American Type Culture Collection (ATCC, Manassas, VA, USA).
  • SK-Mel-28 human melanoma cell line was obtained from Korean Cell Line Bank (KCLB, Seoul, Korea). These cells were maintained at 37 ° C. in EMEM medium (ATCC) containing 10% FBS and antibodies.
  • NHEMs were treated for 48 hours with 50 ng / ml ITAC and total RNA was isolated using TRIZOL reagent (GIbco-BRL, Gaithersburg, MD). 50 ng of total RNA was converted to Cy3 or Cy5-labeled cRNA according to the manufacturer's protocol using the Quick Amp Kit (Agilent Technologies, Palo Alto, Calif.). Absorbance ratios and concentrations at 260 nm and 280 nm were measured using an Agilent Bioanalyzer for qualitative evaluation. The same amount of Cy3- or Cy5-labeled cRNA from another sample was hybridized to Agilent Human Whole Genome 4 ⁇ 44k Microarrays. Data was extracted from the scanned image using Feature Extraction version 10.2 (Agilent Technologies). The hydration reaction was performed twice for each sample.
  • CDNA was synthesized using the Superscript II Reverse Transcriptase Kit (Life Technologies, Grand Island, NY) using 2 ⁇ g total RNA from each sample.
  • TaqMan® probe (Themo Fisher Scientific, Waltham, Mass.) was purchased and qPCR was performed using an ABI Fast Real-Time PCR System (Life Technologies). Relative expression levels of each gene in the sample were normalized using glyceraldehyde 3-phosphate dehydrogenase (GAPDH), a housekeeping gene, and the difference in gene expression between samples was determined using formula 2 - ⁇ Ct . Calculated by
  • Fractalkine a CX3C chemokine, is expressed by dendritic cells and is up-regulated upon dendritic cell maturation.
  • Th2 chemokine, TARC produced by keratinocytes may recruit CLA + CCR4 + lymphocytes into lesional atopic dermatitis skin. J. Invest. Dermatol. 115, 640-646
  • siRNA against HDAC5, HDAC9, JUB, or THBS was transfected into NHEM for 48 hours and total RNA extracted. Scrambled siRNA was used as a negative control. MRNA levels of HDAC5 (a) and HDAC9 (b) in NHEMs were measured by RT-qPCR. Each value was normalized by GAPDH. The data represent 3 independent experiments (*** P ⁇ 0.001).
  • NHEMs were (a) treated with 50ng / ml ITAC for 48 hours or (b) transfected with siRNA against HDAC5. Acetylation levels of alpha-tubulin were measured by Western blot with the indicated antibodies. Scrambled siRNA was used as a control for HDAC5 specific siRNA.
  • NHEMs were treated with 200 ng / ml of MIG, IP-10 or ITAC for 48 hours and total RNA was extracted. MRNA levels of TYR (a), MITF (b), TRP1 (c) and DCT (d) in NHEMs were measured using RT-qPCR. Each value was normalized by GAPDH. The data represent two independent experiments. (* P ⁇ 0.05)
  • NHEMs were transfected 48 hours with scrambled siRNA or siRNA for p53 and further treated with 200 ng / ml ITAC for 48 hours. Each value was normalized by GAPDH. The data represent three independent experiments ( ** P ⁇ 0.01, *** P ⁇ 0.001).

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Abstract

La présente invention concerne et décrit une composition destinée à prévenir ou à traiter le vitiligo ou le vitiligo associé à un mélanome métastatique, la composition comprenant un inhibiteur de chimio-attracteur alpha des lymphocytes T induit par l'interféron (ITAC). La composition peut inhiber le déplacement des cellules formant la mélanine et présenter un effet d'hypopigmentation par inhibition de l'activité de l'ITAC. De plus, la composition peut présenter un effet de prévention ou de traitement du vitiligo ou du vitiligo associé à un mélanome métastatique par inhibition de l'activité de l'ITAC.
PCT/KR2017/007484 2016-07-13 2017-07-12 Composition comprenant un inhibiteur d'itac Ceased WO2018012889A1 (fr)

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WO2023131829A1 (fr) 2022-01-05 2023-07-13 Ramakrishna Reddy Isanaka Formulation pour le traitement de troubles pigmentaires

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US20130216549A1 (en) * 2007-02-28 2013-08-22 Nicolas Fischer Anti-IP-10 Antibodies and Uses Thereof
US20150079099A1 (en) * 2007-08-02 2015-03-19 Novlmmune S.A. Anti-RANTES Antibodies
KR20160015745A (ko) * 2014-07-31 2016-02-15 (주)아모레퍼시픽 케모카인을 함유하는 피부 미백용 조성물

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US20130216549A1 (en) * 2007-02-28 2013-08-22 Nicolas Fischer Anti-IP-10 Antibodies and Uses Thereof
US20150079099A1 (en) * 2007-08-02 2015-03-19 Novlmmune S.A. Anti-RANTES Antibodies
KR20160015745A (ko) * 2014-07-31 2016-02-15 (주)아모레퍼시픽 케모카인을 함유하는 피부 미백용 조성물

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WANG, X. X. ET AL.: "Increased Expression of CXCR3 and Its Ligands in Patients with Vitiligo and CXCL10 as a Potential Clinical Marker for Vitiligo", BRITISH JOURNAL OF DERMATOLOGY, vol. 174, 18 June 2016 (2016-06-18), pages 1318 - 1326, XP055455885 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023131829A1 (fr) 2022-01-05 2023-07-13 Ramakrishna Reddy Isanaka Formulation pour le traitement de troubles pigmentaires

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