KR102563307B1 - Composition for enhancing immune response comprising dcGMP - Google Patents
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Abstract
본 발명은 dcGMP를 유효성분으로 포함하는 면역 증강용 조성물, 식품 조성물, 면역질환 예방 또는 치료용 약학 조성물, 암의 예방 또는 치료용 약학 조성물 및 dcGMP를 NK 세포에 처리하는 단계를 포함하는 시험관 내(in vitro)에서 NK 세포를 활성화하는 방법에 관한 것이다.
본 발명은 dcGMP가 NK 세포의 사멸능 및 NK 수용체 활성을 증가시키고 IFN-γ 발현을 증가시킴으로써 면역 증강 활성을 가지는 것을 구체적으로 확인한 바, 본 발명의 dcGMP를 포함하는 면역 증강용 조성물은 면역 또는 암과 관련한 의약 분야뿐만 아니라 식품, 화장품 등 광범위한 분야에 유용하게 활용될 수 있다.In vitro ( It relates to a method for activating NK cells in vitro .
The present invention specifically confirmed that dcGMP has an immune enhancing activity by increasing NK cell killing ability and NK receptor activity and increasing IFN-γ expression. It can be usefully used in a wide range of fields such as food and cosmetics as well as the pharmaceutical field related to
Description
본 발명은 dcGMP를 유효성분으로 포함하는 면역 증강용 조성물, 식품 조성물, 면역질환 예방 또는 치료용 약학 조성물, 암의 예방 또는 치료용 약학 조성물 및 dcGMP를 NK 세포에 처리하는 단계를 포함하는 시험관 내(in vitro)에서 NK 세포를 활성화하는 방법에 관한 것이다.In vitro ( It relates to a method for activating NK cells in vitro .
면역 반응은 우리 몸을 보호하기 위한 자기방어 기작으로, 외부로부터 유입된 다양한 항원 및 체내 불필요한 대사 산물들을 제거 또는 무력화하는 과정을 포함하고, 항상성을 유지하여 질병의 발생을 억제시키는 역할을 수행한다. 체내 면역 반응은 크게 태어날 때부터 가지고 있는 선천 면역(innate immunity)과 후천적으로 생활 등에 적응되어 얻어지는 후천 면역(acquired immunity)로 구분된다. The immune response is a self-defense mechanism to protect our body, including a process of removing or neutralizing various antigens introduced from the outside and unnecessary metabolites in the body, and plays a role in maintaining homeostasis and suppressing the occurrence of diseases. Immune responses in the body are largely divided into innate immunity, which is present from birth, and acquired immunity, which is acquired through adaptation to life.
선천 면역은 자연 면역이라고도 하며, 항원에 대해 비특이적으로 반응하며 특별한 기억 작용은 보이지 않는다. 이러한 선천 면역은 실제로 대부분의 감염을 방어하는데, 선천적인 면역 체계로는 항원의 침입을 차단하는 피부·점액 조직, 강산성의 위산, 혈액에 존재하는 보체(complement) 등이 있으며, 세포로는 식균 작용을 담당하는 대식세포(macrophage)와 다형핵백혈구(polymorphonuclear leukocyte) 및 NK 세포 등이 있다. Innate immunity, also called innate immunity, responds non-specifically to antigens and does not show any special memory function. This innate immunity actually defends against most infections. The innate immune system includes skin and mucous tissues that block the invasion of antigens, strong acidic stomach acid, and complement present in the blood. Cells include phagocytosis There are macrophages, polymorphonuclear leukocytes, and NK cells responsible for
후천 면역은 적응 면역이라고도 하며, 처음 침입한 항원을 기억하여 다시 침입 시 특이적으로 반응하여 효과적으로 항원을 제거할 수 있다. 이러한 후천 면역은 체액성 면역과 세포성 면역으로 나뉜다. 체액성 면역은 B 림프구가 항원을 인지한 후 분화되어 항체를 분비하고, 이 항체가 주로 감염된 세균을 제거한다. 세포성 면역은 흉선에서 유래한 T 림프구 (T 세포)가 항원을 인지하여 림포카인(lymphokine)을 분비하거나 직접 감염된 세포를 죽이는 역할을 하며, 이러한 세포성 면역은 주로 바이러스 또는 세포 내에서 자랄 수 있는 세균에 감염된 세포를 제거하는 기능을 수행한다.Acquired immunity, also called adaptive immunity, remembers the first invaded antigen and reacts specifically when invaded again to effectively remove the antigen. Such acquired immunity is divided into humoral immunity and cellular immunity. In humoral immunity, after recognizing an antigen, B lymphocytes differentiate and secrete antibodies, and these antibodies mainly eliminate infected bacteria. Cellular immunity plays a role in T lymphocytes (T cells) derived from the thymus recognizing antigens and secreting lymphokine or directly killing infected cells. Such cellular immunity can mainly grow in viruses or cells. It performs the function of removing cells infected with bacteria.
면역 반응에 관여하는 세포들 중 NK 세포(natural killer cell)는 숙주에 감염된 세포나 종양 세포를 직접적으로 공격하는 선천성 면역 반응과 사이토카인 분비를 통하여 세포 독성 T 세포 또는 B 세포를 활성화시키는 후천성 면역 반응에 중요한 역할을 한다 (Advances in Immunology, 2014, 137-170). NK 세포는 IFN이나 대식세포에서 유래된 사이토카인에 의하여 활성화되며, 활성화된 NK 세포는 IFN-γ, TNF-α 등의 사이토카인을 분비하여 종양 세포의 세포 사멸을 촉진하거나 다른 면역세포의 활성화에 기여한다. NK 세포의 활성은 다양한 활성화 및 억제성 수용체가 존재하여 신호전달 균형에 의해 활성이 조절되며, 이러한 조절에 의하여 정상 세포는 공격하지 않고, 감염된 세포를 제거하게 된다 (Cancer Immunol. Immunother. 2014; 63(6): 571-580).Among the cells involved in the immune response, NK cells (natural killer cells) are an innate immune response that directly attacks host-infected cells or tumor cells, and an acquired immune response that activates cytotoxic T cells or B cells through cytokine secretion. (Advances in Immunology, 2014, 137-170). NK cells are activated by IFN or macrophage-derived cytokines, and activated NK cells secrete cytokines such as IFN-γ and TNF-α to promote apoptosis of tumor cells or to activate other immune cells. contribute The activity of NK cells is regulated by the signal transduction balance due to the presence of various activating and inhibitory receptors, and through this regulation, normal cells are not attacked and infected cells are eliminated (Cancer Immunol. Immunother. 2014; 63 (6): 571-580).
NK 세포 활성의 조절은 암 또는 면역질환과 같은 다양한 질병들과 관련이 있음이 알려져 있으며, NK 세포를 이용한 효율적인 면역 증진 방법의 필요성이 대두되고 있다. Regulation of NK cell activity is known to be associated with various diseases such as cancer or immune diseases, and the need for an efficient immune enhancement method using NK cells is emerging.
이러한 배경 하에서, 본 발명자들은 그 기능이 밝혀지지 않은 dcGMP를 NK 세포에 처리 시, NK 세포의 활성이 증가함을 확인하고, 관련 작용 기작을 규명함으로써 본 발명을 완성하였다.Under this background, the present inventors have completed the present invention by confirming that the activity of NK cells increases when NK cells are treated with dcGMP, the function of which is unknown, and by identifying the related mechanism of action.
본 발명의 목적은 dcGMP(deoxy cyclic guanosine monophosphate)를 포함하는 면역 증강용 조성물을 제공하는 것이다.An object of the present invention is to provide a composition for enhancing immunity comprising deoxy cyclic guanosine monophosphate (dcGMP).
본 발명의 다른 하나의 목적은 dcGMP를 유효성분으로 포함하는 면역 증강용 식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a food composition for enhancing immunity comprising dcGMP as an active ingredient.
본 발명의 또 다른 하나의 목적은 dcGMP를 포함하는 면역질환 예방 또는 치료용 약학 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating immune diseases containing dcGMP.
본 발명의 또 다른 하나의 목적은 dcGMP를 포함하는 암의 예방 또는 치료용 약학 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer containing dcGMP.
본 발명의 또 다른 하나의 목적은 dcGMP를 NK 세포에 처리하는 단계를 포함하는 시험관 내(in vitro)에서 NK 세포를 활성화하는 방법을 제공하는 것이다.Another object of the present invention is to provide a method for activating NK cells in vitro comprising the step of treating NK cells with dcGMP.
이를 구체적으로 설명하면 다음과 같다. 한편, 본 발명에서 개시된 각각의 설명 및 실시형태는 각각의 다른 설명 및 실시형태에도 적용될 수 있다. 즉, 본 발명에서 개시된 다양한 요소들의 모든 조합이 본 발명의 범주에 속한다. 또한, 하기 기술된 구체적인 서술에 의하여 본 발명의 범주가 제한된다고 볼 수 없다.A detailed description of this is as follows. Meanwhile, each description and embodiment disclosed in the present invention may also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed herein fall within the scope of the present invention. In addition, it cannot be seen that the scope of the present invention is limited by the specific descriptions described below.
또한, 당해 기술분야의 통상의 지식을 가진 자는 통상의 실험만을 사용하여 본 발명에 기재된 본 발명의 특정 양태에 대한 다수의 등가물을 인지하거나 확인할 수 있다. 또한, 이러한 등가물은 본 발명에 포함되는 것으로 의도된다.In addition, those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Also, such equivalents are intended to be included in this invention.
상기 목적을 달성하기 위한 본 발명의 하나의 양태는 dcGMP(deoxy cyclic guanosine monophosphate)를 유효성분으로 포함하는 면역 증강용 조성물을 제공한다.One aspect of the present invention for achieving the above object provides a composition for enhancing immunity containing dcGMP (deoxy cyclic guanosine monophosphate) as an active ingredient.
본 발명의 "dcGMP(deoxy cyclic guanosine monophosphate)"는 뉴클레오티드 1분자가 고리 형태를 형성하고 있는 구조로서, "고리형 디옥시구아노신 일인산"으로 칭해질 수 있으며, 하기 화학식 1로 표시되는 화합물을 의미한다."dcGMP (deoxy cyclic guanosine monophosphate)" of the present invention is a structure in which one molecule of nucleotide forms a ring, and may be referred to as "cyclic deoxyguanosine monophosphate", and the compound represented by the following formula (1) it means.
상기 dcGMP의 분자량은 351.2, 화학식은 C10H11N5O6P·Na, CAS 번호는 93919-42-7로 알려져 있다. 핵산 유도체인 dcGMP는 cGMP의 유사체이며, cGMP는 세포 내 중요한 생리활성물질로 세포 간 신호 전달 경로에 관여하는 것으로 잘 알려져 있으나, dcGMP의 기능에 대해서는 밝혀진 바 없다. 따라서, dcGMP의 면역 증강 활성에 대해서는 본 발명자들에 의해 처음으로 규명되었다.The molecular weight of the dcGMP is 351.2, the chemical formula is C 10 H 11 N 5 O 6 P·Na, and the CAS number is known as 93919-42-7. The nucleic acid derivative, dcGMP, is an analog of cGMP, and cGMP is an important physiologically active substance in cells and is well known to be involved in intercellular signal transduction pathways. However, the function of dcGMP has not been clarified. Thus, the immune enhancing activity of dcGMP was first identified by the present inventors.
상기 dcGMP의 입수 방법은 특별히 제한되지 않으며, 당업계에 공지된 방법을 이용하여 화학적으로 합성하거나, 시판되는 물질을 사용할 수 있다. 또한, 상기 dcGMP는 용매화된 형태 또는 비용매화된 형태로 존재할 수 있고, 결정형 또는 무정형 형태로 존재할 수 있으며, 이러한 모든 물리적 형태는 본 발명의 범위에 포함된다.The acquisition method of the dcGMP is not particularly limited, and may be chemically synthesized using a method known in the art or a commercially available material may be used. In addition, the dcGMP may exist in a solvated or non-solvated form, and may exist in a crystalline or amorphous form, and all such physical forms are included in the scope of the present invention.
본 발명의 "면역 증강"은 생체의 내부 환경이 외부 인자인 항원에 대한 생체 방어능을 증진시키는 것으로, 상기 면역은 태어날 때부터 지니는 선천면역과 후천적으로 얻어지는 후천면역(획득면역, 적응면역)으로 구분할 수 있고, 상기 면역은 선천면역과 후천면역을 모두 포함하며, 선천면역 또는 선천면역과 후천면역을 함께 증가시키는 것일 수 있으나, 이에 제한되지 않는다."Immune enhancement" of the present invention is to enhance the body's ability to defend against antigens, which are external factors in the internal environment of the body. It can be distinguished, and the immunity includes both innate immunity and acquired immunity, and may increase innate immunity or innate immunity and acquired immunity together, but is not limited thereto.
본 발명의 NK 세포(natural killer cell, 자연 살해 세포)는 면역 세포 중 하나로서 숙주에 감염된 세포나 종양 세포를 직접적으로 공격하는 선천성 면역 반응과 사이토카인 분비를 통하여 세포 독성 T 세포 또는 B 세포를 활성화시키는 후천성 면역 반응에 관여한다. NK 세포는 사이토카인에 의하여 활성화되며, 활성화된 NK 세포는 IFN-γ, TNF-α 등의 사이토카인을 분비하여 종양 세포의 세포 사멸을 촉진하거나 다른 면역세포의 활성화에 기여한다. NK cells (natural killer cells, natural killer cells) of the present invention are one of the immune cells and activate cytotoxic T cells or B cells through an innate immune response that directly attacks host-infected cells or tumor cells and secretion of cytokines Shiki is involved in the acquired immune response. NK cells are activated by cytokines, and activated NK cells secrete cytokines such as IFN-γ and TNF-α to promote apoptosis of tumor cells or to activate other immune cells.
본 발명의 dcGMP는 NK 세포의 활성을 증가시키는 것일 수 있다. 본 발명에서 NK 세포의 활성 증가는 NK 세포의 세포독성 (cytotoxicity) 활성을 증가시키는 것을 의미할 수 있으며, "세포독성 활성" 또는 "사멸능"은 본 명세서에서 혼용되어 사용될 수 있다. The dcGMP of the present invention may increase the activity of NK cells. In the present invention, increasing the activity of NK cells may mean increasing the cytotoxicity (cytotoxicity) activity of NK cells, and "cytotoxic activity" or "killing ability" may be used interchangeably herein.
본 발명의 구체적인 일 구현예에서, 20μm 또는 50μm 농도의 dcGMP를 NK 세포에 처리한 경우, NK의 세포독성 활성이 유의적으로 증가하였으며, 유사한 핵산 유도체인 cAMP 또는 cGMP에 비하여 그 활성이 우수한 것을 확인하였다 (실시예 1).In a specific embodiment of the present invention, when NK cells were treated with dcGMP at a concentration of 20 μm or 50 μm, the cytotoxic activity of NK was significantly increased, and compared to similar nucleic acid derivatives, cAMP or cGMP, the activity was confirmed to be superior (Example 1).
상기 NK 세포는 특정한 항원의 자극 없이 세포 표면의 수용체와 그에 대응하는 표적 세포 리간드의 상호 작용에 의해 기능이 조절되고, 이들 수용체는 크게 활성 수용체와 억제 수용체로 구분된다 (Clinical immunology 2006; 118(1): 1-10). NK 세포에 활성화 신호를 전달하여 NK 세포의 기능을 조절하는 활성화 수용체에는 대표적으로 natural cytotoxicity receptors (NCRs), NKG2D 등이 잘 알려져 있다. 이 중 NCRs은 NKp30, NKp44, NKp46이 밝혀져 있으며, NKp30과 NKp44는 T 세포에서도 발견되지만 NKp46은 NK 세포에서 특이적으로 발현되는 것으로 알려져 있다. NCRs의 발현이 높은 NK 세포의 경우 발현이 적은 세포에 비해 세포독성 능력이 더 높다는 사실이 밝혀져 있어 NCRs의 발현 정도에 따라 NK 세포의 활성화 정도를 확인할 수 있다 (Annual review of immunology 2001; 19: 197-223).The function of the NK cells is regulated by the interaction of cell surface receptors and corresponding target cell ligands without stimulation of specific antigens, and these receptors are largely divided into active receptors and inhibitory receptors (Clinical Immunology 2006; 118(1 ): 1-10). Natural cytotoxicity receptors (NCRs), NKG2D, and the like are well known as representative activating receptors that transmit activation signals to NK cells to regulate NK cell functions. Among these NCRs, NKp30, NKp44, and NKp46 have been identified. NKp30 and NKp44 are also found in T cells, but NKp46 is known to be specifically expressed in NK cells. It has been found that NK cells with high NCRs expression have higher cytotoxicity than cells with low NCRs expression, so the degree of NK cell activation can be confirmed according to the level of NCRs expression (Annual review of immunology 2001; 19: 197 -223).
본 발명에서 NK 세포의 활성 증가는 NK 활성화 수용체 발현의 증가를 통해 달성되는 것일 수 있으며, 상기 NK 활성화 수용체는 NKp30, NKp44 및 NKG2D로 이루어진 군에서 선택되는 하나 이상인 것일 수 있으나, 이에 제한되지 않는다.In the present invention, the increase in NK cell activity may be achieved through an increase in the expression of an NK-activating receptor, and the NK-activating receptor may be one or more selected from the group consisting of NKp30, NKp44, and NKG2D, but is not limited thereto.
본 발명의 구체적인 일 구현예에서 50μm의 dcGMP를 NK 세포에 처리한 결과, cAMP 또는 cGMP에 비하여 NKp30, NKp44, 및 NKG2D의 발현이 증가한 것을 확인한 바 (실시예 2), 본 발명의 dcGMP는 NK 활성화 수용체의 발현 증가를 통해 NK 세포의 활성을 증가시키는 것임을 알 수 있다.In a specific embodiment of the present invention, as a result of treating NK cells with 50 μm of dcGMP, it was confirmed that the expression of NKp30, NKp44, and NKG2D increased compared to cAMP or cGMP (Example 2), dcGMP of the present invention activates NK It can be seen that the activity of NK cells is increased through the increase of receptor expression.
NK 세포는 다양한 사이토카인과 케모카인을 분비하고 항원제시 세포와 직접적인 상호 작용을 통해 후천면역 반응을 활성화 시키는데 중요한 역할을 한다. 특히, 활성화된 NK 세포에서 분비되는 사이토카인인 IFN-γ는 단핵 세포와 수지상 세포를 활성화시키고 성숙시켜 병원균에 대한 선천면역 반응을 증가시키고, Th1 면역 반응 초기에 중요한 역할을 하는 것으로 알려져 있다 (Nature immunology 2008; 9(5): 503-10).NK cells secrete various cytokines and chemokines and play an important role in activating acquired immune responses through direct interaction with antigen-presenting cells. In particular, IFN-γ, a cytokine secreted from activated NK cells, activates and matures monocytes and dendritic cells to increase the innate immune response to pathogens and is known to play an important role in the early stage of the Th1 immune response (Nature Immunology 2008; 9(5): 503-10).
본 발명의 dcGMP는 NK 세포에서 IFN-γ의 분비량을 증가시켜 면역 증강 활성을 나타내는 것일 수 있으나, 이에 제한되지 않는다. The dcGMP of the present invention may exhibit immune enhancing activity by increasing the secretion of IFN-γ in NK cells, but is not limited thereto.
본 발명의 구체적인 일 구현예에서 20μm의 dcGMP를 NK 세포에 처리한 결과, IFN-γ의 발현이 증가한 것을 확인하였다 (실시예 3).In a specific embodiment of the present invention, as a result of treating NK cells with 20 μm of dcGMP, it was confirmed that the expression of IFN-γ increased (Example 3).
NK 세포를 포함한 다양한 면역 세포에서 아데노신 A2B 수용체가 높게 발현된다는 연구가 보고된 바 있으며, 아데노신 수용체를 타겟으로 하는 암 치료 및 면역 반응 증가에 관한 연구가 활발히 진행되고 있다. Studies have reported that adenosine A2B receptors are highly expressed in various immune cells, including NK cells, and studies on cancer treatment and immune response enhancement targeting adenosine receptors are being actively conducted.
이와 관련하여, 본 발명의 구체적인 일 구현예에서는 NK 세포 활성화의 작용 기작을 밝히기 위하여, NK 세포에 dcGMP 처리 후 아데노신 수용체의 mRNA 발현량을 측정한 결과, A2B 수용체의 발현이 증가한 것을 확인하였으며, p38 및 Erk의 인산화가 현저히 증가하는 것을 확인하였다 (실시예 4). 즉, 본 발명의 dcGMP는 NK 세포의 A2B 수용체를 활성화시켜 NK 세포의 활성을 증가시키는 것일 수 있으나, 이에 제한되지 않는다.In this regard, in a specific embodiment of the present invention, in order to reveal the mechanism of action of NK cell activation, as a result of measuring the mRNA expression level of the adenosine receptor after dcGMP treatment of NK cells, it was confirmed that the expression of the A2B receptor increased, p38 and phosphorylation of Erk were significantly increased (Example 4). That is, the dcGMP of the present invention may activate the A2B receptor of NK cells to increase NK cell activity, but is not limited thereto.
본 출원의 조성물은 약학용 조성물, 식품용 조성물, 건강기능식품용 조성물일 수 있으나, 이에 제한되지 않는다. 상기 조성물은 약학적으로 허용 가능한 담체를 추가로 포함할 수 있으며, 담체와 함께 제제화되어 의약품, 식품 및 건강기능식품으로 제공될 수 있다.The composition of the present application may be a pharmaceutical composition, a food composition, or a health functional food composition, but is not limited thereto. The composition may further include a pharmaceutically acceptable carrier, and may be formulated with the carrier and provided as pharmaceuticals, foods, and health functional foods.
본 발명의 다른 하나의 양태는 dcGMP를 유효성분으로 포함하는 면역 증강용 식품 조성물을 제공한다.Another aspect of the present invention provides a food composition for enhancing immunity comprising dcGMP as an active ingredient.
본 발명의 "dcGMP" 및 "면역 증강"에 대한 설명은 전술한 바와 같다.Description of "dcGMP" and "immunity enhancement" of the present invention is as described above.
본 발명의 용어 "식품"은 육류, 소시지, 빵, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알코올음료, 비타민 복합체, 건강기능식품 등의 통상적인 의미의 식품을 모두 포함하며, 본 발명의 dcGMP를 포함할 수 있는 한, 이에 제한되지 않는다. 또한 본 발명의 식품 조성물은 기능성 식품(functional food), 영양 보조제(nutritional supplement), 건강 식품(health food) 및 식품 첨가제(food additives)등의 모든 형태를 포함하여, 상기 유형의 식품 조성물은 당업계에 공지된 통상적인 방법에 따라 다양한 형태로 제조할 수 있다. 상기 식품 조성물의 제조 시에는 당업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있으며, 그 종류는 특별히 제한되지 않는다. 예를 들어, 통상의 식품과 같이 여러 생약 추출물, 식품학적으로 허용 가능한 식품보조첨가제 또는 천연 탄수화물 등을 추가 성분으로 포함할 수 있으며, 이에 제한되지 않는다. 유효 성분의 혼합양은 사용 목적에 따라 적합하게 결정될 수 있다. The term "food" of the present invention refers to meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, chewing gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, It includes all foods in the usual sense, such as vitamin complexes and health functional foods, and is not limited thereto as long as it can include the dcGMP of the present invention. In addition, the food composition of the present invention includes all forms such as functional food, nutritional supplement, health food, and food additives, and the type of food composition is known in the art. It can be prepared in various forms according to conventional methods known to. When preparing the food composition, it may be prepared by adding raw materials and ingredients commonly added in the art, and the type is not particularly limited. For example, as in conventional foods, various herbal extracts, food-acceptable food supplements, or natural carbohydrates may be included as additional components, but are not limited thereto. The mixing amount of the active ingredient can be suitably determined depending on the purpose of use.
구체적인 일 양태로 본 발명의 식품 조성물은 건강기능식품일 수 있다.In a specific aspect, the food composition of the present invention may be a health functional food.
본 발명의 또 다른 하나의 양태는 dcGMP를 유효성분으로 포함하는 면역질환 예방 또는 치료용 약학 조성물을 제공한다.Another aspect of the present invention provides a pharmaceutical composition for preventing or treating immune diseases comprising dcGMP as an active ingredient.
본 발명의 "dcGMP"에 대한 설명은 전술한 바와 같다.Description of the "dcGMP" of the present invention is as described above.
본 발명의 면역질환은 면역계 기능의 이상으로 인하여 발생하는 질병을 통칭하며, NK 세포의 활성 증가를 통해 예방 또는 치료 효과를 얻을 수 있다면 본 발명의 면역 질환의 범주에 포함될 수 있다. NK 세포는 다양한 사이토카인 및 케모카인을 분비하고 항원제시 세포와 직접적인 상호 작용을 통해 후천면역 반응을 활성화 시키며, 활성화된 NK 세포에서 분비되는 사이토카인은 단핵 세포와 수지상 세포를 성숙시켜 병원균에 대한 선천면역 반응을 증가시키고, Th1 면역 반응 초기에 중요한 역할을 하므로, NK 세포의 활성 증가를 통해 면역 질환의 예방 또는 치료 효과를 얻을 수 있음은 자명하다.The immune diseases of the present invention collectively refer to diseases caused by an abnormal immune system function, and if a preventive or therapeutic effect can be obtained through an increase in NK cell activity, it may be included in the scope of the immune diseases of the present invention. NK cells secrete various cytokines and chemokines and activate acquired immune responses through direct interaction with antigen-presenting cells. Since it increases the response and plays an important role in the early stage of the Th1 immune response, it is obvious that the prevention or treatment of immune diseases can be obtained by increasing the activity of NK cells.
구체적으로, 상기 면역질환은 자가면역질환, 바이러스 감염 질환 또는 염증성 질환일 수 있다. 구체적으로, 상기 자가면역질환은 자가면역질환은 크론병, 홍반병, 아토피 피부염, 류마티스 관절염, 하시모토 갑상선염, 악성빈혈, 에디슨씨 병, 제1형 당뇨, 루프스, 만성피로증후군, 섬유근육통, 갑상선기능저하증과 항진증, 경피증, 베체트병, 염증성 장질환, 다발성 경화증, 중증 근무력증, 메니에르 증후군(Meniere's syndrome), 길리안-바레 증후군(Guilian-Barre syndrome), 쇼 그렌 증후군(Sjogren's syndrome), 백반증, 자궁내막증, 건선, 백반증, 전신성 경피증, 천식 또는 궤양성 대장염 등일 수 있으나, 이에 제한되지 않는다.Specifically, the immune disease may be an autoimmune disease, a viral infection disease, or an inflammatory disease. Specifically, the autoimmune diseases include Crohn's disease, erythema, atopic dermatitis, rheumatoid arthritis, Hashimoto's thyroiditis, pernicious anemia, Addison's disease, type 1 diabetes, lupus, chronic fatigue syndrome, fibromyalgia, thyroid function Hypothyroidism and hyperthyroidism, scleroderma, Behcet's disease, inflammatory bowel disease, multiple sclerosis, myasthenia gravis, Meniere's syndrome, Guilian-Barre syndrome, Sjogren's syndrome, vitiligo, endometriosis , psoriasis, vitiligo, systemic scleroderma, asthma or ulcerative colitis, but not limited thereto.
본 발명에서 "예방"이란, 상기 dcGMP를 유효성분으로 포함하는 조성물을 이용하여 면역질환의 발생을 억제 또는 지연시키는 모든 행위를 말한다. 본 발명의 용어 "치료"란, 상기 dcGMP를 유효성분으로 포함하는 조성물을 이용하여 면역질환의 증상을 다스리거나 낫게 하는 모든 행위를 말한다.In the present invention, "prevention" refers to all activities that suppress or delay the occurrence of immune diseases using a composition containing the dcGMP as an active ingredient. The term "treatment" of the present invention refers to all activities of controlling or improving the symptoms of an immune disease using a composition containing the dcGMP as an active ingredient.
본 발명의 "약학 조성물"은 약학적으로 허용되는 담체, 부형제 또는 희석제를 추가로 포함할 수 있다. 이러한 약학적으로 허용되는 담체, 부형제, 또는 희석제는 비자연적으로 발생된 것일 수 있다. 구체적으로, 상기 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 액제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 본 발명에서, 상기 약학 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 제제화 할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 dcGMP에 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘 카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는 데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.The "pharmaceutical composition" of the present invention may further include a pharmaceutically acceptable carrier, excipient or diluent. Such pharmaceutically acceptable carriers, excipients, or diluents may be non-naturally occurring. Specifically, the composition is formulated in the form of oral formulations such as powders, granules, tablets, solutions, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories and sterile injection solutions according to conventional methods, respectively. can be used In the present invention, carriers, excipients and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one excipient in the dcGMP, for example, starch, calcium carbonate, sucrose ( It is prepared by mixing sucrose, lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral use include suspensions, solutions for oral use, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included. there is. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents. As a base for the suppository, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogeratin and the like may be used.
상기 약학 조성물은 목적 또는 필요에 따라 당업계에서 사용되는 통상적인 방법, 투여 경로, 투여량에 따라 적절하게 개체에 투여될 수 있다. 투여 경로의 예로는 경구, 비경구, 피하, 복강 내, 폐 내, 및 비강 내로 투여될 수 있으며, 비경구 주입에는 근육 내, 정맥 내, 동맥 내, 복강 내 또는 피하투여가 포함된다. 또한 당업계에 공지된 방법에 따라 적절한 투여량 및 투여 횟수가 선택될 수 있으며, 실제로 투여되는 본 발명의 약학 조성물의 양 및 투여 횟수는 치료하고자 하는 증상의 종류, 투여 경로, 성별, 건강 상태, 식이, 개체의 연령 및 체중, 및 질환의 중증도와 같은 다양한 인자에 의해 적절하게 결정될 수 있다.The pharmaceutical composition may be appropriately administered to a subject according to a conventional method, administration route, and dosage used in the art according to purpose or necessity. Examples of routes of administration include oral, parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal administration, and parenteral injection includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In addition, an appropriate dosage and frequency of administration may be selected according to a method known in the art, and the amount and frequency of administration of the pharmaceutical composition of the present invention actually administered are the type of symptom to be treated, the route of administration, gender, health condition, It can be appropriately determined by various factors such as diet, the age and weight of the individual, and the severity of the disease.
본 발명에서 dcGMP의 NK 세포 활성화를 통한 면역 증강 활성을 확인한 바, dcGMP를 유효성분으로 포함하는 약학 조성물은 면역질환의 예방 또는 치료 용도로서 유용하게 사용될 수 있다.As the immune enhancing activity of dcGMP through NK cell activation was confirmed in the present invention, a pharmaceutical composition containing dcGMP as an active ingredient can be usefully used for preventing or treating immune diseases.
본 발명의 또 다른 하나의 양태는 dcGMP를 유효성분으로 포함하는 암의 예방 또는 치료용 약학 조성물을 제공한다.Another aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer comprising dcGMP as an active ingredient.
본 발명의 "dcGMP, "예방 또는 치료", 및 "약학 조성물"에 대한 설명은 전술한 바와 같다.Descriptions of "dcGMP, "prevention or treatment", and "pharmaceutical composition" of the present invention are as described above.
본 발명의 암은 정상적인 세포 사멸 균형이 깨지는 경우 세포가 과다 증식하게 됨으로써 생기는 질병을 일컫는다. 이러한 비정상적 과다 증식 세포들은, 경우에 따라 주위 조직 및 장기에 침입하여 종괴를 형성하고, 체내의 정상적인 구조를 파괴하거나 변형시키게 되는데, 이러한 상태를 암이라고 한다.Cancer of the present invention refers to a disease caused by excessive proliferation of cells when the normal cell death balance is broken. These abnormal hyperproliferating cells, in some cases, invade surrounding tissues and organs to form masses, destroying or transforming normal structures in the body, and this condition is called cancer.
상기 암의 종류는 뇌척수종양, 뇌종양, 두경부암, 폐암, 유방암, 흉선종, 중프종, 식도암, 대장암, 간암, 위암, 췌장암, 담도암, 신장암, 방광암, 전립선암, 고환암, 생식세포종, 난소암, 자궁 경부암, 자궁 내막암, 대장암, 림프종, 급성 백혈병, 만성 백혈병, 다발성 골수종, 육종, 악성 흑색종 및 피부암을 포함하나, 이에 제한되지 않는다.The types of cancer include cerebrospinal tumor, brain tumor, head and neck cancer, lung cancer, breast cancer, thymoma, neutrophil tumor, esophageal cancer, colon cancer, liver cancer, stomach cancer, pancreatic cancer, biliary tract cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, germ cell tumor, ovary cancer, cervical cancer, endometrial cancer, colorectal cancer, lymphoma, acute leukemia, chronic leukemia, multiple myeloma, sarcoma, malignant melanoma, and skin cancer.
NK 세포는 표면에 존재하는 다양한 면역 수용체를 통해 암세포와 정상세포를 구분할 수 있으므로, 암세포에 대하여 선택적인 세포 독성을 보인다. 많은 연구를 통해 NK 세포가 암세포를 제거하는데 핵심적인 역할을 함이 규명되었으며, 암환자의 경우 NK세포의 수나 활성에 결함이 있음이 보고되었다 (Hanyang Med Rev 2013: 59-64). 따라서, NK 세포의 활성 증가는 암세포의 제거를 통하여 암의 예방 또는 치료로 이어질 수 있다.Since NK cells can distinguish between cancer cells and normal cells through various immune receptors present on their surface, they exhibit selective cytotoxicity against cancer cells. Many studies have identified that NK cells play a key role in eliminating cancer cells, and it has been reported that cancer patients have defects in the number or activity of NK cells (Hanyang Med Rev 2013: 59-64). Therefore, the increase in activity of NK cells can lead to the prevention or treatment of cancer through the elimination of cancer cells.
본 발명에서 구체적인 일 구현예에서 dcGMP의 NK 세포 활성화 효과를 확인한 바, dcGMP를 유효성분으로 포함하는 약학 조성물은 암의 예방 또는 치료 용도로서 유용하게 사용될 수 있음을 시사한다.In a specific embodiment of the present invention, the NK cell activating effect of dcGMP was confirmed, suggesting that a pharmaceutical composition containing dcGMP as an active ingredient can be usefully used for preventing or treating cancer.
본 발명의 또 다른 하나의 양태는 dcGMP를 NK 세포에 처리하는 단계를 포함하는, 시험관 내(in vitro)에서 NK 세포를 활성화하는 방법을 제공한다.Another aspect of the present invention provides a method for activating NK cells in vitro , comprising the step of treating NK cells with dcGMP.
본 발명의 "dcGMP" 및 "NK 세포"에 대한 설명은 전술한 바와 같다.Description of the "dcGMP" and "NK cells" of the present invention is as described above.
본 발명에서 dcGMP의 처리는 당업계에서 통상적인 방법에 따라 수행될 수 있으며, dcGMP의 처리 농도는 1 내지 100μm, 1 내지 90μm, 1 내지 80μm, 1 내지 70μm, 1 내지 60μm 일 수 있으나, 이에 제한되지 않는다.In the present invention, the treatment of dcGMP may be performed according to a conventional method in the art, and the treatment concentration of dcGMP may be 1 to 100 μm, 1 to 90 μm, 1 to 80 μm, 1 to 70 μm, and 1 to 60 μm, but is limited thereto. It doesn't work.
본 발명의 "시험관 내(in vitro)"는 살아있는 생명체 내부가 아니라 시험관과 같이 제어가 가능한 환경에서 수행되는 실험 과정을 말한다. 상기 시험관 내부의 환경에서는 다양한 변인을 용이하게 통제할 수 있어 효율적으로 결과를 확인할 수 있다." In vitro " of the present invention refers to an experimental process performed in a controllable environment such as a test tube rather than inside a living organism. In the environment inside the test tube, various variables can be easily controlled, and the results can be efficiently confirmed.
본 발명의 구체적인 일 구현예에서 상기 dcGMP는 NK 세포에 처리되어 NK 세포의 세포독성 활성을 증가시키고, NK 활성화 수용체의 발현을 증가시키며, IFN-γ의 분비량을 증가시키는 것을 확인한 바, 이는 시험관 내(in vitro)에서 dcGMP가 NK 세포를 활성화할 수 있음을 시사한다.In a specific embodiment of the present invention, the dcGMP was confirmed to increase the cytotoxic activity of NK cells by treating NK cells, increase the expression of NK-activating receptors, and increase the amount of IFN-γ secretion, which is ( in vitro ) suggests that dcGMP can activate NK cells.
본 발명은 dcGMP가 NK 세포의 사멸능 및 NK 수용체 활성을 증가시키고 IFN-γ 발현을 증가시킴으로써 면역 증강 활성을 가지는 것을 구체적으로 확인한 바, 본 발명의 dcGMP를 포함하는 면역 증강용 조성물은 면역 또는 암과 관련한 의약 분야뿐만 아니라 식품, 화장품 등 광범위한 분야에 유용하게 활용될 수 있다.The present invention specifically confirmed that dcGMP has an immune enhancing activity by increasing NK cell killing ability and NK receptor activity and increasing IFN-γ expression. It can be usefully used in a wide range of fields such as food and cosmetics as well as the pharmaceutical field related to
도 1은 dcGMP 처리에 따른 NK 세포의 세포독성 활성을 분석한 도이다.
도 2는 cAMP, cGMP, 및 dcGMP 처리에 따른 NK 세포의 세포독성 활성을 비교한 도이다.
도 3은 cAMP, cGMP, 및 dcGMP가 NK 수용체 발현에 미치는 영향을 확인한 도로서, 도 3a는 FACS 분석의 MFI 값을 비교한 그래프이며, 도 3b는 FACS 분석 데이터이다.
도 4는 cAMP, cGMP, 및 dcGMP가 IFN-γ의 발현에 미치는 영향을 확인한 도로서, 도 4a는 FACS 분석의 MFI 값을 비교한 그래프이며, 도 4b는 FACS 분석 데이터이다.
도 5는 dcGMP가 A2B 수용체 및 A2A 수용체 발현에 미치는 영향을 확인한 도이다.
도 6은 A2B 수용체의 하위 마커의 발현 수준을 확인한 도로서, 도 6a는 p38 및 Erk의 웨스턴 블랏 데이터이며, 도 6b는 웨스턴 블랏 결과를 정량화 한 그래프이다.1 is a diagram of analyzing the cytotoxic activity of NK cells according to dcGMP treatment.
Figure 2 is a diagram comparing the cytotoxic activity of NK cells according to cAMP, cGMP, and dcGMP treatment.
3 is a diagram confirming the effect of cAMP, cGMP, and dcGMP on NK receptor expression, FIG. 3a is a graph comparing MFI values of FACS analysis, and FIG. 3b is FACS analysis data.
Figure 4 is a diagram confirming the effect of cAMP, cGMP, and dcGMP on the expression of IFN-γ, Figure 4a is a graph comparing MFI values of FACS analysis, Figure 4b is FACS analysis data.
5 is a diagram confirming the effect of dcGMP on A2B receptor and A2A receptor expression.
Figure 6 is a diagram confirming the expression levels of sub-markers of the A2B receptor, Figure 6a is western blot data of p38 and Erk, and Figure 6b is a graph quantifying the western blot results.
이하, 실시예를 통하여 본 발명을 보다 상세히 설명하고자 한다. 이들 실시예는 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through examples. These examples are intended to explain the present invention in more detail, and the scope of the present invention is not limited by these examples.
실시예 1. dcGMP의 NK 세포의 활성에 미치는 영향 확인Example 1. Confirmation of the effect of dcGMP on the activity of NK cells
NK92 세포에 24시간 동안 IL-2 starvation을 수행한다. 그 후, 6 well에 2×105/ml로 cell seeding을 하고, cAMP, cGMP, dcGMP를 20μM, 50μM로 처리하여 24시간 동안 배양한 후 실험을 수행하였다. NK92 cells were subjected to IL-2 starvation for 24 hours. Thereafter, cell seeding was performed in 6 wells at 2×10 5 /ml, and cAMP, cGMP, and dcGMP were treated with 20 μM and 50 μM, cultured for 24 hours, and experiments were performed.
NK 세포 활성 분석은 calcein-AM 방출 분석법을 사용하여 평가하였다. K562 표적 세포를 calcein으로 1시간 동안 표지하고, 표지화 된 표적 세포 (1×104 개 세포)와 개수 비율에 따라 희석된 NK92 세포를 96 well round bottom plate에서 4시간 동안 배양하였다. “maximum release”는 표적 세포에 4% Triton X-100을, “minimum release”에는 표적 세포에 배양 배지를 첨가하여 실험하였다. 상층액으로 방출된 calcein은 multi-mode microplate reader를 사용하여 측정하였다. NK 세포의 활성 분석은 calcein release %=(sample release－spontaneous release)/(maximum release－spontaneous release)×100으로 계산하여 나타내었다.NK cell activity assay was evaluated using the calcein-AM release assay. K562 target cells were labeled with calcein for 1 hour, and the labeled target cells (1×10 4 cells) and diluted NK92 cells according to the number ratio were cultured in a 96 well round bottom plate for 4 hours. “Maximum release” was tested by adding 4% Triton X-100 to target cells, and “minimum release” by adding culture medium to target cells. Calcein released into the supernatant was measured using a multi-mode microplate reader. The activity analysis of NK cells was calculated and expressed as calcein release %=(sample release−spontaneous release)/(maximum release−spontaneous release)×100.
그 결과, dcGMP를 20μm 및 50μm 처리한 경우 모두 대조군에 비하여 NK 세포의 사멸능이 증가한 것을 확인하였다 (도 1). 또한, cAMP, cGMP, 및 dcGMP를 각각 처리한 NK 세포의 사멸능을 비교한 결과, dcGMP가 가장 높은 사멸능을 나타내었다 (도 2). 즉, dcGMP는 NK 세포의 활성을 현저하게 증가시키는 것을 알 수 있었다.As a result, it was confirmed that the apoptotic ability of NK cells was increased compared to the control group when dcGMP was treated with 20 μm and 50 μm (FIG. 1). In addition, as a result of comparing the apoptosis of NK cells treated with cAMP, cGMP, and dcGMP, respectively, dcGMP showed the highest apoptosis (FIG. 2). That is, it was found that dcGMP markedly increased the activity of NK cells.
실시예 2. dcGMP의 NK 수용체 발현에 미치는 영향 확인Example 2. Confirmation of the effect of dcGMP on NK receptor expression
24시간 동안 cAMP, cGMP, 및 dcGMP로 stimulation 한 NK92 세포를 적절한 항체로 염색하여 분석하였다. 표면 염색의 경우, PE-anti-NKp30, PE-anti-NKp44, APC-anti-NKG2D를 사용하였다. 샘플의 데이터는 Canto II에서 얻었으며, 분석은 소프트웨어 FlowJo를 사용하여 MFI (mean fluorescence intensity) 값으로 나타내었다. NK92 cells stimulated with cAMP, cGMP, and dcGMP for 24 hours were analyzed by staining with appropriate antibodies. For surface staining, PE-anti-NKp30, PE-anti-NKp44, and APC-anti-NKG2D were used. The data of the samples were obtained in Canto II and analysis was expressed as mean fluorescence intensity (MFI) values using the software FlowJo.
NK 세포의 활성에는 다양한 활성화 또는 저해성 수용체가 관여하는데, NK92 세포에 dcGMP를 50μM 처리한 결과, cAMP 또는 cGMP에 비하여 활성화 수용체인 NKp30, NKp44, NKG2D의 발현이 증가한 것을 확인하였다 (도 3).Various activating or inhibitory receptors are involved in the activity of NK cells. As a result of treating NK92 cells with 50 μM of dcGMP, it was confirmed that the expression of NKp30, NKp44, and NKG2D, which are activating receptors, increased compared to cAMP or cGMP (FIG. 3).
실시예 3. dcGMP의 IFN-γ의 발현에 미치는 영향 확인Example 3. Confirmation of the effect of dcGMP on the expression of IFN-γ
상기 실시예 2의 방법과 동일한 방법으로 IFN-γ의 발현을 측정하였다. IFN-γ는 NK 세포에서 분비되는 사이토카인으로서 선천면역 반응을 증가시키고 후천면역 반응을 활성화 시키는데 중요한 역할을 한다. NK92 cell에 dcGMP를 20μM 처리한 결과, 면역활성인자인 IFN-γ의 발현이 증가한 것을 확인하였다 (도 4).Expression of IFN-γ was measured in the same manner as in Example 2 above. IFN-γ is a cytokine secreted by NK cells and plays an important role in increasing the innate immune response and activating the acquired immune response. As a result of treating NK92 cells with 20 μM of dcGMP, it was confirmed that the expression of IFN-γ, an immunoactive factor, increased (FIG. 4).
실시예 4. NK 세포 활성화의 작용 기작 분석Example 4. Analysis of the mechanism of action of NK cell activation
NK 세포 활성화의 작용 기작을 밝히기 위하여, NK 세포에서 발현되는 아데노신 수용체의 mRNA 발현량을 측정하였다. NK 세포에 dcGMP를 처리한 결과, NK 세포에서 발현되는 수용체 중 A2B 수용체의 발현은 증가하였으나, A2A 수용체의 발현은 감소한 것을 확인하였다 (도 5).In order to elucidate the mechanism of activation of NK cells, the amount of mRNA expression of adenosine receptors expressed in NK cells was measured. As a result of treating NK cells with dcGMP, it was confirmed that the expression of the A2B receptor among receptors expressed in NK cells increased, but the expression of the A2A receptor decreased (FIG. 5).
이와 관련하여, A2B 수용체의 하위 마커인 p38 및 Erk의 발현 수준을 확인하기 위하여 웨스턴 블랏을 수행하였다. 구체적으로, 24시간 동안 dcGMP로 stimulation 한 NK92 세포를 protease inhibitor, phosphatase inhibitor를 포함한 RIPA 버퍼에 용해시켰다. 그 후, 동일한 양의 단백질을 10% SDS PAGE로 분리하고, polyvinylidene difluoride membrane으로 트랜스퍼 하였다. 5% 스킴 밀크로 1시간 동안 블로킹을 수행하고, 1차 항체를 overnight으로 인큐베이션 하였다. 이 때 사용한 1차 항체로는, extracellular signal-regulated kinase (ERK), phosphorylated (p-)ERK, p38, p-p38을 사용하였다. 이어서, membrane을 PBST로 세척하고, 상응하는 HRP 접합 된 2차 rabbit 항체와 함께 실온에서 1시간 동안 배양하였다. 각 밴드의 강도는 프로그램 CSAnalyzer 4를 사용하여 얻었으며, phosphorylation form을 total form으로 정량화하였다.In this regard, Western blotting was performed to confirm the expression levels of p38 and Erk, submarkers of the A2B receptor. Specifically, NK92 cells stimulated with dcGMP for 24 hours were lysed in RIPA buffer containing protease inhibitor and phosphatase inhibitor. Then, the same amount of protein was separated by 10% SDS PAGE and transferred to a polyvinylidene difluoride membrane. Blocking was performed with 5% skim milk for 1 hour, and the primary antibody was incubated overnight. As the primary antibodies used at this time, extracellular signal-regulated kinase (ERK), phosphorylated (p-)ERK, p38, and p-p38 were used. Then, the membrane was washed with PBST and incubated with the corresponding HRP-conjugated secondary rabbit antibody for 1 hour at room temperature. The intensity of each band was obtained using the program CSAnalyzer 4, and the phosphorylation form was quantified as the total form.
A2B 수용체의 하위 마커인 p38 및 Erk의 발현 수준을 확인한 결과, dcGMP의 처리 시 p38 및 Erk의 인산화가 현저히 증가하는 것을 확인하였다. 이를 통해, 본 발명에서는 dcGMP는 NK 세포의 A2B 수용체를 활성화시켜 NK 세포의 활성을 증가시키는 것임을 규명하였다 (도 6).As a result of confirming the expression levels of p38 and Erk, which are submarkers of the A2B receptor, it was confirmed that the phosphorylation of p38 and Erk significantly increased when treated with dcGMP. Through this, in the present invention, it was found that dcGMP activates the A2B receptor of NK cells to increase NK cell activity (FIG. 6).
이상의 설명으로부터, 본 발명이 속하는 기술분야의 당업자는 본 발명이 그 기술적 사상이나 필수적 특징을 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 이와 관련하여, 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적인 것이 아닌 것으로 이해해야만 한다. 본 발명의 범위는 상기 상세한 설명보다는 후술하는 청구범위의 의미 및 범위 그리고 그 등가 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.From the above description, those skilled in the art to which the present invention pertains will be able to understand that the present invention may be embodied in other specific forms without changing its technical spirit or essential features. In this regard, it should be understood that the embodiments described above are illustrative in all respects and not limiting. The scope of the present invention should be construed as including all changes or modifications derived from the meaning and scope of the following claims and their equivalent concepts rather than the detailed description above.
Claims (10)
상기 면역 증강은 NK 세포의 활성 증가인 것인, 면역 증강용 식품 조성물.
A food composition for enhancing immunity containing dcGMP (deoxy cyclic guanosine monophosphate) as an active ingredient,
The immune enhancement is to increase the activity of NK cells, immune enhancement food composition.
The food composition for enhancing immunity according to claim 1, wherein the increase in activity of NK cells increases the expression of NK activating receptors.
The food composition for enhancing immunity according to claim 3, wherein the NK-activating receptor is at least one selected from the group consisting of NKp30, NKp44 and NKG2D.
The food composition for enhancing immunity according to claim 1, wherein the dcGMP increases the secretion of IFN-γ in NK cells.
A method of activating NK cells in vitro , comprising the step of treating NK cells with dcGMP.
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| WO2012154975A2 (en) * | 2011-05-11 | 2012-11-15 | Stc.Unm | Nitric oxide/cgmp pathway inhibition of vla-4 related cell adhesion |
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