WordNet

limit, block, or decrease the action or function of; "inhibit the action of the enzyme"; "inhibit the rate of a chemical reaction"
control and refrain from showing; of emotions, desires, impulses, or behavior (同)bottle up, suppress
limit the range or extent of; "Contact between the young was inhibited by strict social customs"
the 3rd letter of the Roman alphabet (同)c
(music) the keynote of the scale of C major
a general-purpose programing language closely associated with the UNIX operating system
a substance that retards or stops an activity

PrepTutorEJDIC

〈感情・欲望・行動・作用など〉‘を'抑制する / (…しないように)〈人〉‘を'抑制する,妨げる《+『名』+『from』+『名』(do『ing』)》
carbonの化学記号
抑制する人(物) / 化学反応抑制剤

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/04/04 21:11:44」(JST)

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C1-inhibitor (C1-inh, C1 esterase inhibitor) is a protease inhibitor belonging to the serpin superfamily. Its main function is the inhibition of the complement system to prevent spontaneous activation.^[1]^[2] C1-inhibitor is an acute-phase protein that circulates in blood at levels of around 0.25 g/L. The levels rise ~2-fold during inflammation. C1-inhibitor irreversibly binds to and inactivates C1r and C1s proteases in the C1 complex of classical pathway of complement. MASP-1 and MASP-2 proteases in MBL complexes of the lectin pathway are also inactivated. This way, C1-inhibitor prevents the proteolytic cleavage of later complement components C4 and C2 by C1 and MBL. Although named after its complement inhibitory activity, C1-inhibitor also inhibits proteases of the fibrinolytic, clotting, and kinin pathways. Note that C1-inhibitor is the most important physiological inhibitor of plasma kallikrein, fXIa, and fXIIa.

Proteomics

C1-inhibitor is the largest member among the serpin superfamily of proteins. It can be noted that, unlike most family members, C1-inhibitor has a 2-domain structure. The C-terminal serpin domain is similar to other serpins, which is the part of C1-inhibitor that provides the inhibitory activity. The N-terminal domain (also some times referred to as the N-terminal tail) is not essential for C1-inhibitor to inhibit proteases. This domain has no similarity to other proteins. C1-inhibitor is highly glycosylated, bearing both N- and O-glycans. N-terminal domain is especially heavily glycosylated.^[2]

Genetics

The human C1-inhibitor gene (SERPING1) is located on the eleventh chromosome (11q11-q13.1).^[3]^[4]

Role in disease

Deficiency of this protein is associated with hereditary angioedema ("hereditary angioneurotic edema"), or swelling due to leakage of fluid from blood vessels into connective tissue.^[5] Deficiency of C1-inhibitor permits plasma kallikrein activation, which leads to the production of the vasoactive peptide bradykinin. Also, C4 and C2 cleavage goes unchecked, resulting in auto-activation of the complement system. In its most common form, it presents as marked swelling of the face, mouth and/or airway that occurs spontaneously or to minimal triggers (such as mild trauma), but such swelling can occur in any part of the body. In 85% of the cases, the levels of C1-inhibitor are low, while in 15% the protein circulates in normal amounts but it is dysfunctional. In addition to the episodes of facial swelling and/or abdominal pain, it also predisposes to autoimmune diseases, most markedly lupus erythematosus, due to its consumptive effect on complement factors 3 and 4. Mutations in the gene that codes for C1-inhibitor, SERPING1, may also play a role in the development of age related macular degeneration.^[6]

Despite uncontrolled auto-activation, it is important to note that levels of key complement components are low during an acute attack, because they are being consumed - indeed, low levels of C4 are a key diagnostic test for hereditary angioedema. This situation is analogous to the low levels of clotting factors found in disseminated intravascular coagulation (DIC).

Classification

There are three types of C1 inhibitor deficiency:^[7]

Type I: Hereditary. Three of the four genes for C1 inhibitor are null genes, leading to low levels of C1 inhibitor.
Type II: Hereditary. There are high levels of C1 inhibitor, but it is non-functional.
Type III: Hereditary or acquired. Related to hormone levels in the body.

Therapeutic use

In hereditary angioedema

People with frequent attacks of angioedema are often treated using attenuated androgens, such as danazol and oxandrolone. Blood-derived C1-inhibitor may be more effective and does not carry the side-effects of danazol such as virilization and a risk of liver tumors, but does carry the risk associated with the use of any human blood product. Cinryze, a pharmaceutical-grade C1-inhibitor, was approved for the use of HAE in 2008. It was also the first C1-inhibitor approved for use in the United States.^[8] It is a highly purified, pasteurized and nanofiltered plasma-derived C1 esterase inhibitor product; it has been approved for routine prophylaxis against angioedema attacks in adolescent and adult patients with HAE.^[9]

A recombinant C1 inhibitor obtained from the milk of transgenic rabbits, conestat alfa (trade name Ruconest), is approved for the treatment of acute HAE attacks in adults.^[10]^[11]

While C1 inhibitor therapy has been used acutely for more than 35 years in Europe in patients with C1 inhibitor deficiency, new methods of treating acute attacks have emerged: a plasma kallikrein inhibitor and the bradykinin receptor antagonist icatibant.

For other conditions

The activation of the complement cascade can cause damage to cells, therefore the inhibition of the complement cascade can work as a medicine in certain conditions.^[12] When someone has a heart attack, for instance, the lack of oxygen in heart cells causes necrosis in heart cells: Dying heart cells spill their contents in the extracellular environment, which triggers the complement cascade. Activation of the complement cascade attracts phagocytes that leak peroxide and other reagents, which may increase the damage for the surviving heart cells. Inhibition of the complement cascade can decrease this damage.

Synthesis

C1-inhibitor is contained in the human blood; it can, therefore, be isolated from donated blood. Risks of infectious disease transmission (viruses, prions, etc.) and relative expense of isolation prevented widespread use. It is also possible to produce it by recombinant technology, but Escherichia coli (the most commonly used organism for this purpose) lacks the eukaryotic ability to glycosylate proteins; as C1-inhibitor is particularly heavily glycosylated, this asialylated recombinant form would have a short circulatory life (the carbohydrates are not relevant to the inhibitor function). Therefore, C1-inhibitor has also been produced in glycosylated form using transgenic rabbits.^[13] This form of recombinant C1-inhibitor also has been given orphan drug status for delayed graft function following organ transplantation and for capillary leakage syndrome.^[14]

References

^ Davis AE (September 2004). "Biological effects of C1 inhibitor". Drug News Perspect. 17 (7): 439–46. doi:10.1358/dnp.2004.17.7.863703. PMID 15514703.
^ ^a ^b Cicardi M, Zingale L, Zanichelli A, Pappalardo E, Cicardi B (November 2005). "C1 inhibitor: molecular and clinical aspects". Springer Semin. Immunopathol. 27 (3): 286–98. doi:10.1007/s00281-005-0001-4. PMID 16267649.
^ Theriault A, Whaley K, McPhaden AR, Boyd E, Connor JM (April 1990). "Regional assignment of the human C1-inhibitor gene to 11q11-q13.1". Hum. Genet. 84 (5): 477–9. doi:10.1007/BF00195824. PMID 2323781.
^ Carter PE, Duponchel C, Tosi M, Fothergill JE (April 1991). "Complete nucleotide sequence of the gene for human C1 inhibitor with an unusually high density of Alu elements". Eur. J. Biochem. 197 (2): 301–8. doi:10.1111/j.1432-1033.1991.tb15911.x. PMID 2026152.
^ Davis AE (January 2008). "Hereditary angioedema: a current state-of-the-art review, III: mechanisms of hereditary angioedema". Ann. Allergy Asthma Immunol. 100 (1 Suppl 2): S7–12. doi:10.1016/S1081-1206(10)60580-7. PMID 18220146.
^ Ennis S, Jomary C, Mullins R, Cree A, Chen X, Macleod A, Jones S, Collins A, Stone E, Lotery A (November 2008). "Association between the SERPING1 gene and age-related macular degeneration: a two-stage case-control study". Lancet 372 (9652): 1828–34. doi:10.1016/S0140-6736(08)61348-3. PMID 18842294.
^ Gompels, MM; Lock, RJ; Abinun, M; Bethune, CA; Davies, G; Grattan, C; Fay, AC; Longhurst, HJ; et al. (2005). "C1 inhibitor deficiency: consensus document" (pdf). Clinical and experimental immunology 139 (3): 379–94. doi:10.1111/j.1365-2249.2005.02726.x. PMC 1809312. PMID 15730382. Retrieved 2010-05-17.
^ "Approval History, Letters, Reviews and Related Documents - CINRYZE". Retrieved 2015-01-21.
^ Drugs.com: Cinryze
^ Drugs.com: Ruconest 2100 U powder for solution for injection
^ Summary of product characteristics for Ruconest
^ Caliezi C, Wuillemin WA, Zeerleder S, Redondo M, Eisele B, Hack CE (March 2000). "C1-Esterase inhibitor: an anti-inflammatory agent and its potential use in the treatment of diseases other than hereditary angioedema". Pharmacol. Rev. 52 (1): 91–112. PMID 10699156.
^ Koles K, van Berkel PH, Pieper FR, Nuijens JH, Mannesse ML, Vliegenthart JF, Kamerling JP (January 2004). "N- and O-glycans of recombinant human C1 inhibitor expressed in the milk of transgenic rabbits". Glycobiology 14 (1): 51–64. doi:10.1093/glycob/cwh010. PMID 14514717.
^ Bernstein JA (January 2008). "Hereditary angioedema: a current state-of-the-art review, VIII: current status of emerging therapies". Ann. Allergy Asthma Immunol. 100 (1 Suppl 2): S41–6. doi:10.1016/S1081-1206(10)60585-6. PMID 18220151.

External links

The MEROPS online database for peptidases and their inhibitors: I04.024
B02AB03

UpToDate Contents

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1. 後天性C1インヒビター欠損症：臨床症状、疫学、病因、および診断 acquired c1 inhibitor deficiency clinical manifestations epidemiology pathogenesis and diagnosis
2. C1阻害剤正常を示す遺伝性血管性浮腫（III型HAE） hereditary angioedema with normal c1 inhibitor type iii hae
3. 後天性C1インヒビター欠損症：管理および予後 acquired c1 inhibitor deficiency management and prognosis
4. 遺伝性血管浮腫：急性発作の治療 hereditary angioedema treatment of acute attacks
5. 血管浮腫の概要：病因と原因 an overview of angioedema pathogenesis and causes

English Journal

3,5,3'triiodo-L-thyronine induces SREBP-1 expression by non-genomic actions in human HEP G2 cells.

Gnoni GV, Rochira A, Leone A, Damiano F, Marsigliante S, Siculella L.SourceLaboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Prov.le Lecce-Monteroni, Lecce, Italy. gabriele.gnoni@unisalento.it
Journal of cellular physiology.J Cell Physiol.2012 Jun;227(6):2388-97. doi: 10.1002/jcp.22974.
Liver is an important target for thyroid hormone actions. T(3) exerts its effects by two mechanisms: (i) Genomic actions consisting of T(3) link to nuclear receptors that bind responsive elements in the promoter of target genes, (ii) non-genomic actions including integrin αvb3 receptor-mediated MAP
PMID 21826653

Identification of new biomarkers for Down's syndrome in maternal plasma.

Heywood W, Mills K, Wang D, Hogg J, Madgett TE, Avent ND, S Chitty L.SourceClinical & Molecular Genetics Unit, UCL Institute of Child Health, University College London, UK.
Journal of proteomics.J Proteomics.2012 May 17;75(9):2621-8. Epub 2012 Mar 18.
Using ProteinChip Technology (SELDI TOF MS), the maternal plasma of 53 chromosomally-normal control and 28 Down's syndrome affected pregnancies was profiled between 10 and 20weeks' gestation. Preliminary studies demonstrated two distinct phases of changes in protein expression, the first at 10-14wee
PMID 22456345

Japanese Journal

Mechanism of Fcγ Receptor-Mediated Trogocytosis-Based False-Positive Results in Flow Cytometry

Masuda Sakiko,Iwasaki Sari,Tomaru Utano,Sato Juri,Kawakami Ai,Ichijo Kana,Sogo Sayuri,Baba Tomohisa,Katsumata Kazuaki,Kasahara Masanori,Ishizu Akihiro
PLoS One 7(12), e52918, 2012-12-27
… however, the C1 inhibitor did not yield an obvious influence on FcγR-mediated trogocytosis. … On the other hand, although immunoglobulin ought to be resistant to heat inactivation, the inhibitor of human anti-mouse antibodies (HAMA) effectively blocked FcγR-mediated trogocytosis. …
NAID 120005183187

帝王切開後に遺伝性血管性浮腫による顔面浮腫を来した1症例

富田有毅彦,亀井政孝,重城聡 [他]
麻酔 61(12), 1376-1379, 2012-12-00
NAID 40019513015

補体系の役割と臨床医学でのトピックス

若宮伸隆
臨床病理 60(8), 779-785, 2012-08-25
NAID 10031123890

Related Pictures

Pasteurized and nanofiltered, plasma-derived C1 esterase inhibitor concentrate for the Pathways inhibited by C1-esterase inhibitor (C1INH) (reproduced from | Download C1 Inhibitor Hereditary Angioedema - Dermatology - Medbullets Step 2/3 [Full text] Self-administered C1 esterase inhibitor concentrates for the managemen | PPA Human C1 inhibitor ELISA Kit (ab224883) | アブカム Native Human C1 inhibitor protein (ab285825) | アブカム Hereditair angio-oedeem (C1-esterase remmer deficientie)

★リンクテーブル★

リンク元	「古典的経路」「C1インヒビター」
拡張検索	「complement C1 inhibitor protein」「C1 inhibitor deficiency」
関連記事	「inhibit」「C」「inhibitor」「C1」

「古典的経路」

Serpin peptidase inhibitor, clade G (C1 inhibitor), member 1
	C1-inhibitor
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	1M6Q, 2OAY
Identifiers
Symbols	SERPING1 ; C1IN; C1INH; C1NH; HAE1; HAE2
External IDs	OMIM: 606860 MGI: 894696 HomoloGene: 44 GeneCards: SERPING1 Gene
Gene ontology
Molecular function	• serine-type endopeptidase inhibitor activity; • protein binding;
Cellular component	• extracellular region; • extracellular space; • platelet alpha granule lumen; • extracellular exosome; • blood microparticle;
Biological process	• negative regulation of complement activation, lectin pathway; • platelet degranulation; • complement activation, classical pathway; • aging; • blood coagulation; • blood coagulation, intrinsic pathway; • blood circulation; • negative regulation of endopeptidase activity; • platelet activation; • fibrinolysis; • innate immune response;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	v; t; e;