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1 대한내분비학회지 : 제 21 권제 5 호 2006 지상강좌 내분비 - 대사질환에서 NF-κB 의최신지견 성균관대학교의과대학내과학교실, 동국대학교의과대학내과학교실 1 이명식 김경아 1 NF-κB Pathway in Metabolic/endocrine Diseases Myung-Shik Lee, Kyoung-Ah Kim 1 Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine; and Department of Medicine 1, Ilsan International Hospital, Dongguk University School of Medicine 서 NF-κB는 1986년 David Baltimore 등에의해 B 림프구에서 κ chain enhancer protein로발견되었다. 당시 Baltimore 등은 electrophoretic mobility shift assay (EMSA) 라는검사방법을창안하여 enhancer element에결합하여전사 (transcription) 를조절하는전사인자라는새로운종류의분자 (molecule) 를발견하게된것이다 [1]. 이는그후수많은종류의전사인자를발견하는효시가된새발견이었으며, 이미 1975년에역전사효소 (reverse transcriptase) 의발견으로노벨의학상을수상한 David Baltimore의또하나의기념비적업적이라할수있다. NF-κB는처음에는 B 림프구특이인자로생각되었으나, 추후의연구에의하여극소수의세포를제외하고각종조직에서거의어디에나발현되며염증, 면역 (immunity), 세포자연사 (apoptosis), 발암 (carcinogenesis), 조직재생등다양한기능을수행함이알려지게되었다. 특히세포자연사에관한기능은 NF-κB가비면역계세포 (nonimmune cell) 에서어떠한기능을수행하는지에대한중요한단서를제공하는것으로, 위에서언급한바와같이최초에 NF-κB가면역세포에서발견된것으로부터 NF-B의염증, 면역에관한기능이유추될수있는반면, 비면역계세포에서도 NF-κB가발견되면서그기능에관한의문이있어왔기때문이다. 본논문에서는 NF-κB 활성화의기본개념을소개하고암, 당뇨병및죽상경화증등내분비질환의발병에관련된 NF-κB의새로운지견을소개하고자한다. 1. NF-κB 의활성화경로 (activation pathway) 와염증 NF-κB는위에서살펴본바와같이 EMSA를통하여 B-cell-specific intronic light chain enhancer의이동도 론 (mobility) 를지연하는역할로처음기술되었으며, LPS (lipopolysaccharide), TNF (tumor necrosis factor), PMA (phorbol 12-myristate 13-acetate) 등각종자극에의해활성화되는어디에나있는인자 (ubiquitous factor) 이다. NF-κ B의구성성분으로는 p65 (RelA), C-rel, RelB, NF-B1 (p50/105), NF-B2 (p52/100) 등이있으며, 공통적으로 DNA 결합, 이합체화 (dimerization), IκB (inhibitor of NF-κB) 와의상호작용등의기능을수행하는 Rel homology domain (RHD) 을갖는다. NF-κB의활성화경로는오랫동안수수께끼로남아있었으나, 1997년 Michael Karin 등에의해 IKK (IκB kinase) 가발견됨으로써해결의실마리가풀리게되었다 [2]. 현재 NF-κB의상위 kinase인 IKK complex는 α, β, γ 3개의성분으로구성되어있다고생각되며, α, β 2개의촉매아단위 (catalytic subunit) 중에서 IKKβ 아단위는 NF-κB의정규 (canonical) 활성화경로에서필수적인역할을하고, IKKα는비정규 (noncanonical) 활성화경로에관여하며, 비촉매아단위 (noncatalytic subunit) 인 IKKγ (NEMO) 는조절역할을한다고생각된다 [3]. 즉정규활성화경로는 TNFα, IL (Interleukin)-1, LPS, dsdna에 IKKβ가활성화되어 IκB 를세린인산화시키고, 인산화된 IκBα는유비퀴틴화 (ubiquitination) 에의해분해되어복합물을이루고있던 p65(rela):p50 이합체 (dimer) 가유리되어세포질로부터핵으로이동하여핵안에서전사인자로작용하게된다. 한편 lymphotoxin 또는 BAFF (B cell-activating factor) 로자극되는비정규활성화경로에서는 IKKα가활성화되어 p100을인산화, 분해시켜 p52로변환시키고, 이에따라 RelB:p52 이합체가활성화된다. 정규활성화경로는선천면역 (innate immunity) 또는염증에관여하며, 비정규활성화경로는임파계기관형성 (lymphoid organogenesis), B 세포성숙, 적응면역에관여한다 (Fig. 1). 최근에 IKK/NF-κB 경로를자극하는대표적물질인 LPS,

2 - 이명식외 1인 : 내분비-대사질환에서 NF-κB의최신지견 - Fig. 1. Activation of two NF-κB signaling pathways. Activation of NF-κB by immune stimuli involves canonical and noncanonical pathways, which are based on degradation of IκB or processing of p100, respectively. The canonical pathway is stimulated by diverse cellular stimuli, such as antigens and cytokines, and is dependent on the trimeric IKK complex. The noncanonical pathway responds to a subset of TNF family members, including BAFF and CD40L, and requires IKKα but not IKKγ or IKKβ. BAFF; B cell activating factor. dsdna 등이 NF-κB를활성화시키는수용체및그기전이소상히밝혀지게되었다. 즉초파리 (drosophila) 에서등-배극성 (dorsal-ventral polarity) 에관련된 toll[4] 의 mammalian paralogue인 toll-like receptor (TLR) 가상기세균산물 (bacterial product) 의수용체이고자연면역을조절하는중요한수용체임이밝혀졌으며 [5], 그하위 (downstream) 로 MyD88 (myeloid differentiation marker 88), TRIF (TIR domain-containing adaptor inducing interferon-β), IKK, NF-κB, IRF-3 (interferon regulatory factor), STAT1 (signal transducer and activator of transcription) 등이순차적으로활성화됨이밝혀지게되었다 [6]. 2. 비면역계세포에서항세포자연사인자로서의 NF-κB (NF-κB as an antiapoptotic factor in nonimmune cells) NF-κB가면역세포이외에도비면역계세포에서발현됨은이미알려져왔으나, 비면역계세포에서의기능이분명하게밝혀지게된것은 knockout mouse 연구를통해서였다. Beg 등은 p65 결핍생쥐를제조한결과태생기에죽는것을관찰하였는데, 그원인은간세포의자연적인세포자연사에의한간부전이었다 [7]. 이후연구에의해간조직에서는태 생기및태아기에 TNFα가다량분비되며이에의해간세포의세포자연사가올조건이형성되며, 이때 TNFα에의해 p65를위주로하는 NF-κB 활성화가동시에일어나 TNFα에의해유도되는세포자연사가억제되고있음을알게되었다. 실제거의모든일차세포 (primary cell) 또는배양된세포는 TNFα에의해사멸되지않는데, 그이유는바로동시에 TNFα 에의해유도되는 NF-κB 의활성화가일어나기때문이다 [8~10]. 간세포사멸에의한간부전및태생기치사 (embryonic lethality) 는 IKKβ 결핍생쥐에서도관찰되어 IKK/NF-κB 경로가 in vivo에서세포사멸 (cell death) 을막는중요한역할을하는것을다시한번보여주고있다 [11]. 이 NF-κB의항세포자연사활동 (antiapoptotic activity) 은그후많은세포또는조직의 in vitro 및 in vivo 실험에서증명되어, 현재비면역계세포에서의 NF-κB의가장중요한기능중의하나는항세포자연사임이널리인정되고있다. 즉 in vivo에서염증또는면역이일어날때 TNFα 등의염증매개체에의해주위의비면역계세포들이손상을받을수있으며, 이비면역계세포에대한방관자세포상해 (bystander cell injury) 를막는기능을 NF-κB가수행한다고볼수있다. NF-κB의항세포자연사기능은비면역계세포에만국한되는것은아니고면역세포에서도관찰된다. 즉대식세포

3 대한내분비학회지 : 제 21 권제 5 호 2006 (macrophage) 가탄저균독소 (anthrax toxin) 에의해세포사멸을거칠때 NF-κB가항세포자연사기능을수행하는것이보고된바있다 [12]. 그러나 LPS에의한 TLR4 자극에의해대식세포가자극되는경우에는 NF-κB 활성화가항세포자연사인자로서중요한역할을수행하지않고, caspase 활성화가세포사멸을막는역할을하여 caspase 억제제가존재하면대식세포가급속한괴사로진행하게되어, 기존에 caspase가세포사멸을일으킨다는이론과는다른결과를보여준다 [13]. 3. 갑상선암세포사멸에서의 NF-κB (NF-κB in thyroid cancer cell death) 위에서살펴본 NF-κB의항세포자연사기능은각종의암세포에서뚜렷이관찰되고있으며, 바로이이유로인해암세포는대부분 TNFα에의한세포사멸에저항력이있고 TNFα 발견당시의기대와달리 TNFα는항암물질로유용성이없다. 한예로서 ME-180 cervical cancer cell ( 자궁경부암세포 ) 은 TNFα 단독으로는세포사멸을유도할수없는데 nondegradable superrepressor IκBα 로핵산전달감염 (transfection) 시키던지또는 IκBα 의프로테아좀분해 (proteasomal degradation) 를억제하는 MG132로전처치후 TNFα 처리를하면세포사멸이유도되어 IκBα 분해와그에의한 NF-κB 활성화가 TNFα에의한세포사멸을억제함을보여주었다 [14]. 또한 TNFα와 IFNγ ( 또는 IFNα) 를같이처리하여도 ME-180 암세포사멸을일으킬수있는데, 이때 IFNγ가 TNFα에의한 NF-κB 활성화를억제함으로써 TNFα에대한저항을극복함이 reporter assay를통해관찰되었다. 그러나 IFNγ가 TNFα 처리후의 p65의핵전위 (nuclear translocation) 나 EMSA에서의 mobility shift를직접억제하지는못하여, 아마도 IFNγ에의해유도되는 STAT1 등의전사인자등이 squelching effect를통하여 p65에의한전사촉진 (transactivation) 을억제하는것으로생각된다 [14,15]. TNFα가대부분의암세포에서세포사멸을유도하지못하는것과는달리최근에발견된새로운 TNF계구성원인 TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) 은 2종류의 death receptor (DR4, DR5) 를통하여대부분의암세포에대하여강력한세포자연사활동을갖는다 [16,17]. 반면에정상세포에대해서는이러한세포사멸을유발하지않아진행된암에대한새로운치료제로서의가능성이매우높은유망한물질로생각된다 [16,18]. TRAIL에의한세포자연사의경우 caspase와미토콘드리아가중요한역할을한다고알려져있으나 [19~21], 어떻게 TRAIL이암세포에선택적으로세포자연사를유도하는지명확히규명되지않았으며, 더구나특정암세포는 TRAIL에저항성을나타내는데그분자기전또한명확하지않다. TRAIL에의한 NF-κB 활성화에관해서도처음에는 TNFα와는달리 NF-κB 활성화 를일으키지않는다는설이우세하였으나 [22,23], 그후 NFκB가 delayed activation된다는보고들도있어이론의여지가있다 [22,24,25]. 저자들은 TRAIL이 FRO anaplastic thyroid cancer cell ( 갑상선역형성암세포 ) 과 SK-Hep1 hepatoma cell ( 간암세포 ) 에서 NF-κB 활성화를시키는지그리고그것이세포사멸과어떠한연관이있는지조사하였다. 그결과 TRAIL이 p65를 Asp 97 위치에서분할 (cleavage) 시켜 NF-κB의활성화를억제하고, 따라서 NF-κB에의한항세포자연사가차단되는것이밝혀졌으며, 결국 caspase에의한 p65 분열및 NF-κB 활성화의억제가 TRAIL이강력한세포자연사활동을갖는하나의이유가됨을알수있었다 [26]. 한편 NF-κB 활성화의항세포자연사기능은발암현상에서도중요한역할을할수있는것으로생각된다. 즉장상피세포 (intestinal epithelial cell) 에특이적으로 IKKβ/NF-κB가억제되면장상피세포의세포자연사가증가하며, 이때대장염 (colitis) 에의해유발되는대장암의발생이감소하게되어결국 NF-κB에의한암세포의세포자연사에대한저항성이발암현상의일정단계에서암세포성장에영향을미치는것으로생각된다 [27]. 4. 제 1 형당뇨병에서 NF-κB (NF-κB and type 1 diabetes) TNFα는가장중요한세포사멸효과물질 (death effector molecule) 의하나이지만, 대개의일차세포나무한증식세포 (immortalized cell) 들은 TNFα 단독에의한세포자연사에영향을받지않는데, 그이유는 TNFα에의해항세포자연사과정의활성화도부수적으로수반되기때문이다 [9,10,28]. NF-κB가 TNFα에의해유발되는표적세포의세포자연사를방지하는데중요한역할을하는것으로알려져왔다 [8,29,30]. 그러나이와는반대로신경세포나림프구를이용한실험에서는저산소손상 (hypoxic injury) 또는 reactive oxygen species (ROS) 에의한세포사멸시 NF-κB 활성화가세포자연사를조장한다는것이보고되었다 [31,32]. 췌장소도에서도 IL-1β에의해활성화된 NF-κB는세포자연사를조장한다고보고되어있다 [33~37]. 이러한서로상이한결과는세포사멸효과물질, 세포종류, 사용된세포사멸의방식차이에기인할수있다. 실제로최근에는 UV나항암제처리후 NF-κB에의해항세포자연사관련유전자표현이억제됨이보고되고있는데이는 TNFα 처리때와는다른결과들이다 [38]. NF-κB의역할에대해서상반된보고들이있기때문에본실험실에서는 IFNγ/TNFα synergism 모델을적용해췌장소도세포사멸과제1형당뇨병에서 NF-κB 활성화의역할에대해연구했다. TNFα는 MIN6N8 인슐린종 (insulinoma) 세포주에서 IκB 분해를유발하고 p65을세포질로부터핵으로전위시킨다. 또한인슐린종세포주에서 EMSA 실험을통해

4 - 이명식외 1인 : 내분비-대사질환에서 NF-κB의최신지견 - TNFα에의한 NF-κB DNA-binding nuclear complex의활성화를볼수있었고, 이는 p65와 p50 아단위로이루어져있었다. IFNγ로전처리를해도 TNFα에의해유도된 NF-κB 활성화에영향을미치지못하였다. 한편인슐린종세포또는일차췌도세포에서는 TNFα에의해세포자연사가일어나지않지만, MG132로전처리하여 p65의핵전위및 NF-κB 활성화를억제하는경우에는 TNFα에처리에의한세포자연사가유도되었다. 인슐린종세포주에서 IκB superrepressor' (I κbα-sr) 를핵산전달감염또는아데노바이러스에의한형질도입 (transduction) 시 NF-κB 활성화만특이적으로억제되는데, 이때 TNFα에의해유도되는세포자연사에민감하게됨을알수있었다. 이러한결과들은 TNFα에의한췌장베타세포사멸에서 NF-κB 활성화에따른보호역할을시사하며 NF-κB가 TNFα에대하여항세포자연사역할을하는것을의미한다. 위에서언급된 in vitro 실험결과처럼 in vivo 에서도 TNFα에의한췌장베타세포사멸을 NF-κB 활성화로인해막을수있다면, in vivo에서제1형당뇨병발생시 NF-κB 활성화를방지하는기전이존재해야한다. 일부세포타입에서는 IFNγ가 TNFα에의한 NF-κB 활성화를억제하지만 [36,39], MIN6N8 인슐린종세포주에서는 IFNγ가 TNF α에의해유도되는 NF-κB 활성화에영향을미치지못했다 [40]. IFNγ가인슐린종세포주에서 TNFα에의한 NF-κB 활성화를억제하지못하지만, IFNγ는 IAP (inhibitor of apoptosis) 또는 TRAF (tumor necrosis factor receptor-associated factors) 같은 NF-κB에의해활성화되는항세포자연사기구를억제시킬수도있다 [41]. 제1형당뇨병의베타세포사멸에서 NF-κB의 in vivo 역할을규명하기위해본실험실에서는췌장베타세포에서 superrepressor' IκBα를발현시킨생쥐 (RIP-mIκBα mice) 를만들었다. miκbα 생쥐의췌장소도세포는 TNFα나 IFNγ /TNFα에의한세포사멸에민감하였으나, IFNγ/IL-1β에는덜민감하였다. RIP-mIκBα 생쥐의소도에 TNFα 처리시 ciap1, XIAP, TRAF2의증가가억제되었다. RIP-mIκBα NOD mouse는당뇨병발생이증가하였고, 베타세포의세포자연사도증가하였다. RIP-mIκBα NOD mouse에 diabetogenic CD4 + T 세포를입양전달 (adoptive transfer) 시당뇨병발생이증가하였고, 이때항-TNFα 중화항체 (neutralizing anti -TNFα antibody) 를처리시당뇨병발생이줄었다. 이러한결과는 in vivo에서 NF-κB가베타세포에항세포자연사의역할을하며, 자가면역당뇨병의발병에 TNFα가중요함을다시한번시사한다 [42]. 그러나실제 in vivo 상황은제1형당뇨병발생과정의여러단계에서 membranous/soluble ( 막 / 가용성 ) 형태의시토카인 (cytokine) 과다른종류의세포사멸효과물질이서로다른농도로공존하는등다양한자극이존재한다. 기존의보고들은췌장베타세포사멸에서 IL-1β나산화질소 (nitric oxide) 를세포사멸효과물질로보고한바있다 [43~45]. IL-1β가 in vivo 1형당뇨병발생의췌장베타세포사멸에서중요한세포사멸효과물질이라면 IL-1β에의한 NF-κB 활성화는췌장소도세포에유해하여야할것이고 [33,35~37], 이는 TNFα에의한 NF-κB 활성화와는반대로작용하게된다. 또한동질한무한증식세포로구성된인슐린종세포주에서와는달리일차췌도세포는다양한세포로구성되어있기때문에시토카인에대한반응이다를수있다 [46,47]. 예를들어췌장소도에존재또는침윤하는단핵세포들은 TNFα에반응해 IL-1β같은시토카인을생성할수있다. 췌도세포에서의 NF-κB가췌도세포사멸을방지하여제1형당뇨병의발생을억제할수있는것과는달리염증세포에서의 NF-κB 활성화는염증의증폭기 (amplifier) 로작용하여자가면역을증가시키고질병의경과를촉진할가능성이있다. 즉 NF-κB의역할은다른시스템과마찬가지로제1형당뇨병에서도면역시스템과비면역계시스템에서다를가능성이있는것이다. 따라서 NF-κB가당뇨병의발생에기여할지또는억제할지는아직알수없는데, 이는 NF-κB 활성을조정하는항당뇨병약물을개발하는데있어서중요한이슈가될수있다. 5. NF-κB 와제 2 형당뇨병 (NF-κB and type 2 diabetes) 제2형당뇨병과 NF-κB가연관이있다는사실은 2형당뇨병의발생이많은부분인슐린저항성에의하고이는경도의염증과연관이있음에서기인한다. 인슐린저항성과염증과의상관성은 Hotamisligil 등에의해제시되었는데, 이들은지방조직에서 TNFα가생성되고 TNFα가인슐린수용체 (insulin receptor, IR) 와인슐린수용체기질 (insulin receptor substrate, IRS) 의신호전달을억제한다는것을밝혔다 [48~50]. 사람의인슐린저항성을매개하는데있어 TNFα가어느정도관여할것이냐는아직의견이분분하지만, 이들의발견은인슐린저항성이염증 (TNFα) 과대사신호 (metabolic signal) (IR/IRS) 간의 cross-talk에기인한다는것을제시했다. 이런배경에서염증매개자에의해활성화되는 IKKβ/NF-κB 염증경로가인슐린저항성을유발할수있는유력한매개체로알려졌다. 역사적으로도 20세기초에살리실산나트륨 (sodium salicylate) 이당뇨병치료제로제시되었다 [51]. 이후 IKKβ가살리실산의직접적인표적임이밝혀졌다 [52]. 염증에의해다양한 serine-, threonine-directed kinase가활성화되고 (inflammation-activated kinase), 이는 IR 또는 IRS의세린 / 트레오닌인산화를유발해인슐린저항성을일으킨다 (Fig. 2). 염증과인슐린저항성과의상관관계를보기위한후보물질로 IKKβ 억제제인살리실산을이용한실험모델이제시되어왔다 [53]. 첫째, 심한인슐린저항성을보이는 obese

5 대한내분비학회지 : 제 21 권제 5 호 2006 Fig. 2. Proposed model of metabolic and inflammatory signaling and sensing pathways in adipocytes, macrophages and hepatocytes. Adipocytes secrete factors that attract monocytes and lead to differentiation of monocytes into resident macrophages. Together, adipocytes and macrophages interact, increasing circulating proinflammatory cytokines, promoting a chronic, systemic inflammatory response that adversely affects metabolic function and leads to diabetes. Inflammatory pathways can be initiated by extracellular mediators such as cytokines and lipids or by intracellular stresses such as ER stress or excess ROS production by mitochondria. Signals from all of these mediators converge on inflammatory signaling pathways, including IKK. Key initiating events in the liver are 1) hepatic activation of serine/threonine kinases (IKK), which presumably caused insulin resistance at the IRS-1/2 level, and 2) the activation of the IKK/IκBα /NF-κB pathway (via PKC, ROS, or other mechanisms), leading to expression and secretion of inflammatory cytokines (TNFα, IL-1, IL-6, and MCP-1). ICAM, intercellular adhesion molecule; IL-6, interleukin-6; IR, insulin receptor; IRS, insulin receptor substrate; MCP-1, monocyte chemoattractant protein-1; M-CSF, macrophage colony-stimulating factor; MIF, macrophage migration inhibitory factor MIP, macrophage inflammatory protein; PAI-1, plasminogen activator inhibitor-1; TNF-α, tumor necrosis factor-α. rodent model (Zucker fatty rats, ob/ob mice) 에서아스피린과살리실산은인슐린저항성을감소시키고, 이동물모델의간, 근육조직에서인슐린신호전달이회복됨이증명되었다. 둘째, 3T3-L1 ( 지방 ), Fao ( 간 ) 세포주에서 TNFα와 calyculin A ( 세린 / 트레오닌인산분해요소억제제 ) 처리후살리실산이인슐린저항성을회복시킬수있었다. HEK 293 세포주에서 IKKβ를과발현시키면인슐린수용체활성화를억제하고 dominant inhibitory IKKβ는 TNFα에의한인슐린저항성을막을수있었다. 셋째, in vivo에서 IKKβ level의상대적인감소에의한인슐린감수성정도를보기위해이형 (heterozygous) IKKβ +/- 쥐에서혈당과인슐린이감소했음이증명되었고, IKKβ +/- 생쥐와 ob/ob 생쥐를교배시에도대조군에비해혈당이낮았다. 따라서 IKKβ의 gene dosage, 단 백질의감소에의해혈당의감소와인슐린감수성의호전이따른다는것이증명되었다 [53]. 지방주입에의한인슐린저항성발생모델에서 intralipid 주입에따른혈장유리지방산의급격한상승은간과근육에서인슐린저항성을유발한다 [54,55]. 이때 PKC isoform들이활성화되고, 이는 IKKβ/NF-κB 경로를활성화한다 [56,57]. 쥐에서살리실산처리후지방주입시또는 IKKβ 이형결핍생쥐에서지방주입시인슐린저항성발생이경미했다 [58]. 제2형당뇨병환자에있어고용량아스피린 (~7 g/day) 을사용한인슐린저항성개선에있어서 basal hepatic glucose production이 ~20% 감소하고, insulin-stimulated peripheral glucose disposal이 ~20% 호전되었다. 또한공복혈당, 총콜레스테롤, C-reactive protein, 공복중성지방과유리지방산의감

6 - 이명식외 1인 : 내분비-대사질환에서 NF-κB의최신지견 - Table 1. Comparison of NF-κB tissue-specific knockout or transgenic mouse models Tissue Manupulation Phenotype Weight gain Glucose, Insulin, Cytokine * (IL-1β, IL-6, References FFA, Leptin TNFα) Myeloid IKKβ lacking in myeloid cells (Ikbkb mye ) (on HFD) Protected from hepatic insulin resistance Same S,, n/c,n/c,s,s [61] Liver (1)IKKβ lacking in hepatocytes (Ikbkb hep ) (on HFD) (2)Liver-specific transgenic expression of activated IKKβ (LIKK) (on a chow diet) (3)Liver-specific transgenic expression of activated IκB superrepressor (LISR) (on HFD) Muscle (1)Muscle-specific IKKβ knockout (on gold thioglucose treatment) (2)Muscle-specific transgenic expression of activated IKKβ (MIKK) (on a chow diet) Pancreas Islet-specific transgenic expression of activated IκB superrepressor (RIP-mIκBα) Adipose Not reported tissue Potected from hepatic insulin resistance Develop insulin resistance in liver & muscle Protected from insulin resistance Develop insulin resistance Comparable to control Muscle wasting Normal in terms of insulin sensitivity Protected against islet apoptosis n/c S,, S,n/c,S,S [61] Same S,, S,S S,, S [60] Same n/c,, S,S (on chow) n/c [60] Same S, S, n/c, S n/c [89] Muscle dystrophy S, S,, n/c n/c [62] Same n/c n/c [42] The different mouse models have various age- and diet-dependent responses; therefore, for simplicity, the descriptions are for the adult phenotype on a described diet and compared to wild-type on the same diet. HFD, high fat diet; FFA, free fatty acid; S, similar to control; n/c, no comment. * plasma. 소가관찰되어인슐린저항성의호전이있음이보고되었다 [59]. 그렇다면 IKKβ 억제에의한인슐린감수성개선에있어실제로중요한조직이무엇인가에대해 tissue-specific knockout 또는 overexpression mouse가설명해줄수있다 (Table 1). 인슐린저항성은주로인슐린반응조직인간, 근육, 지방조직에서문제를일으킨다. Liver-specific IKKβ transgenic mouse (LIKK) 에서는간, 근육조직에서인슐린저항성이발생하고, 혈장 IL-6이증가하며 anti-il-6으로중화시인슐린저항성이호전되었다고보고되어있다. 반면 liver-specific IκBα superrepressor transgenic mouse는고지방식이로비만을유발시같은비만도의대조군에비해인슐린저항성발생이경미했다 [60]. Karin 등은 liver-specific IKKβ deletion mouse 모델에서고지방식이또는 ob/ob 생쥐와의교배로비만유발시같은비만도의대조군에비해인슐린저항성발생이경미하고혈장 IL-1 증가도경미하며, 간조직에서의인슐린저항성발생이경미함을보고하였다. 그러나근육에서는인슐린저항성개선이없었다 [61]. 흥미롭게도골수세포에서 IKKβ를결핍시킨생쥐모델에서도같은현상을보이며, 이모델에서는근육에서도인슐린저항성개선이있으므로골수세포에서생성되는염증매개자가인슐 린반응조직에서영향을미칠가능성이있다 [61]. 반면 muscle-specific IKKβ- transgenic mouse (MIKK) 또는 muscle-specific IκBα superrepressor transgenic mouse (MISR) 에서는인슐린저항성이발생또는억제되지않았다. MIKK mouse에선근육위축이일어나며 MISR mouse는근육에서특별한표현형이관찰되지는않았다 [62]. 한편, 고지방식이에의한비만생쥐또는 LIKK mouse의간조직에서는 NF-κB 경로와연관있는수용체중 IL-1, IL-6, IL-8, TNF 수용체외에 TLR2와 TLR4의증가가관찰되었다 [60]. TLR4는박테리아에서유래되는 LPS 같은외인성리간드로도활성화되지만, 호스트에서유래되는내인성염증리간드인 HSP60 (heat-shock protein 60), fibronectin extradomain A, hyaluronan 등에의해서도활성화되어 NFκB를활성화시키고대표적인염증질환인죽종형성 (atherogenesis) 발생에도관여한다 [63]. TLR4 +/- mouse는식이에의해유도된인슐린저항성발생이경미하다는보고가있어, TLR4가특정한내인성리간드에의해활성화되고그로인한 NF-κB의활성과이로인한인슐린저항성발생기전이있음을시사한다

7 대한내분비학회지 : 제 21 권제 5 호 2006 Fig. 3. Schematic representation of atherogenesis. Indicated are the different cell types involved and the different steps in the atherosclerotic process potentially affected by NF-B activation. (1)Initiation of atherosclerosis is characterized by the formation of modified LDL (mldl), followed by the subsequent activation of endothelial cells and secretion of chemokines. On migration through the endothelial layer, the monocytes differentiate into macrophages and scavenge the modified LDL from the vessel wall, resulting in (2) foam cell formation. Persistent hypercholesterolemia leads to intracellular accumulation of cholesteryl esters and eventually apoptosis and release of proinflammatory oxidized lipid derivatives into the plaque, further exacerbating the (3)inflammatory responses. (4), (5) Later stages involve the formation of a fibrotic cap through proliferation and migration of smooth muscle cells and cell death resulting in a necrotic core. SR indicates scavenger receptor. Modified from reference[88]. 6. NF-κB 와죽상경화증 (NF-κB and atherosclerosis) 죽상경화증은일종의경미한염증질환 (low-grade inflammatory disease) 이라고생각되므로, 생체내의죽상경화증에서염증의주요매개자인 NF-κB가중요한역할을한다는가설이제시된것은이해가되는일이다. 혈액중의단핵세포또는일부혈관평활근세포에서유래된지질을섭취한포말세포 (foam cell) 가혈관벽에침착되고, 여러종류의케모카인 (chemokine), 시토카인과성장인자를생성한다. 이런인자들이이주세포 (immigrating cell) 또는상주세포 (resident cell) 의전환과분화를조절하고섬유판 (fibrous plaque) 형성에관여하게된다. 이러한염증과정에관여된주요조절자로 NF-κB가 proatherogenic 인자로알려져왔고죽상경화증과연관된 proinflammatory 유전자를조절한다. 사람의죽상경화증병변에서혈관내피세포, 대식세포, 혈관평활근세포에서 NF-κB가활성화되어있다 [64]. 또한쥐의대동맥에풍선으로손상을준후에혈관평활근세포의증식이활발한부위에서 NF-κB의활성이관찰됨이보고되어있다 [65]. 죽상경화증은오랜기간을걸쳐발생하는데, 이에는 (1) 초기병변의발생, (2) 혈액중의단핵세포또는일부혈관평활근세포에서유래된지질을섭취한포말세포의혈관벽침착, (3) 염증반응, (4) 세포사멸, (5) 혈관평활근세포증식과 fibrous cap 형성의단계가있다 (Fig. 3). NF-κB의역할도이러한각각의단계와또한각각의세포마다달라서죽상경화증의초기병변형성단계에서는내피세포및대식세포에서, 또한후기병변에서는혈관평활근세포에서활성화되는데이때에는여러자극에의해유도되며이런자극들에는혈관손상같은국소적인자, modified LDL (low-density lipoprotein), 병변에서방출되는시토카인, 고혈당에의한최종당화산물, cytomegalovirus나 chlamydia 같은병원체들이있다. 죽상경화증발생의초기단계에서는혈관벽에서 LDL의변형 (modification) 이일어나며, modified LDL은혈관벽에서의국소적염증반응을일으킨다. 이때 NF-κB는 LDL 변형, 염증성지방매개체생성에관여하는 group IIa secretory phospholipase A2[66], 5-lipoxygenase, 12-lipoxygenase[67] 를조절한다. Modified LDL은내피세포에서 NF-κB를활성화시켜 monocyte chemoattractant protein-1 (MCP-1) 분비

8 - 이명식외 1인 : 내분비-대사질환에서 NF-κB의최신지견 - 를증가시켜병변으로단핵세포의침투를유도하고, P-selectin, E-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1 (VCAM-1) 같은부착분자 (adhesion molecule) 를조절한다. 단핵세포가일단내피세포층밑으로들어오게되면분화과정을거쳐혈관조직의대식세포의특성을지니게되는데, 이때는혈관내피세포나대식세포자체의 NF-κB가대식세집락자극인자 (macrophage colony-stimulating factor) 를조절해대식세포로의분화를촉진시킨다 [68,69]. 한편단핵세포 / 대식세포의조직침투를위해선세포외기질을분해해야되는데, 이때 NF-κ가 metalloproteinase-9를조절한다 [70-72]. 또한대식세포의콜레스테롤유입과유출에관여하는 scavenger receptor class A (SR-A), ATP-binding cassette transporter 1 (ABCA1) 을조절한다. 죽상경화증의염증반응단계에서는 NF-κB가활성화시키는 proinflammatory 또는 proatherogenic 시토카인으로 IL-1β, IL-12, IFNγ 등이알려져있다. 그러나염증시토카인이죽상경화증에영향을미치는기전은아직잘밝혀지지않고있다. IL-1β 결핍생쥐의경우죽상경화증발생이줄어드는데, 이생쥐에선 MCP-1, VCAM-1의감소가동반되고있다 [73]. 반면 NF-κB가항염증 (anti-inflammation) 과정에관여한다는보고가있는데 [74], 이는죽상경화증모델에서도 NF-κB 가항염증시토카인인 IL-10를 upregulation시켜죽상경화증을억제할수있다 [75~79]. 또한 proinflammatory 시토카인인 IL-6는항죽종형성 (anti-atherogenic) 시토카인으로알려져있어 [80], NF-κB에의해조절되는시토카인의역할을해석할때는전신적인효과와죽상경화증병변에국한되는국소적효과를구별해야할필요가있다. 죽상경화증발생의후기단계에선세포사멸이중요한이슈가될수있는데, 이런관점에서 NF-κB는포말세포의세포자연사를방지해죽상경화판의안정성을유지해서항죽종형성효과를나타낼수있다 [81]. 또한상당히진행된죽상경화병변에선 NF-κB가평활근세포의증식을일으키고 [82~85], 이로인해 fibrous cap 형성을일으켜동맥경화판의안정성를유지해항죽종형성효과로나타낸다. 한편죽상경화증발생의주요원인인당뇨병에서는병변의진행이빠른것이특징인데, 이에기여하는인자로는고혈당, 과다응고 (hypercoagulability), 이상지질혈증, 고인슐린혈증등을들수있다. 고혈당은세포내 ROS 생성을증가시키며, 이에따라 NF-κB경로가활성화되면염증반응에관련된물질들의분비가증가되고혈전생성을증가시키는인자들이증가하게된다 [86]. 쥐의대동맥에서혈관평활근세포를채취하여이를다양한농도의포도당으로처리하여본결과를보면, 고농도포도당에의한평활근세포의증식에있어 NF-κB가활성화되어있고, 이를 IκBα superrepressor' 아데노바이러스로차단하면평활근세포증식및혈전생성 을증가시키는인자인 plasminogen activator inhibitor-1 (PAI-1) 의발현이억제되는것이관찰되고있어 [87], 고혈당에의한혈관평활근세포의증식및 PAI-1 발현에있어 NFκB가중요한역할을할가능성이있다. 이와같이죽상경화증에서 NF-κB는 proatherogenic으로작용할뿐만아니라 antiatherogenic으로도작용하므로 NF-κB 를표적으로하는치료제개발에있어서는세포 -특이적또는질병발생단계 -특이적수준에서고려가되어야할것이다. 참고문헌 1. Sen R, Baltimore D: Inducibility of kappa immunoglobulin enhancer-binding protein NF-kappa B by a posttranslational mechanism. Cell 47: , DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M: A cytokine-responsive IkB kinase that activates the transcriptional factor NF-kB. Nature 388: , Lin A, Karin M: NF-kB in cancer: a marked target. Semin Cancer Biol 13: , Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA: The dorsoventral regulatory gene cassette spatzle/toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86: , Medzhitov R, Preston-Hurlburt P, Janeway CA: A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388: , Beulter B: Inferences, questions and possibilities in Toll-like receptor signalling. Nature 430: , Beg AA, Sha WC, Bronson RI, Ghosh S, Baltimore D: Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kB. Nature 376: , Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin AS: NF-kB antiapoptosis: induction of TRAF1 and TRAF2 and c-iap1 and c-iap2 to suppress caspase-8 activation. Science 281: , Wang CY, Mayo MW, Baldwin AS: TNF- and cancer-therapy-induced apoptosis: potentiation by inhibition of NF-kB. Science 274: , Beg AA, Baltimore D: An essential role for NF-kB in

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