Английская Википедия:Interleukin 1-alpha

Interleukin-1 alpha (IL-1 alpha) also known as hematopoietin 1 is a cytokine of the interleukin 1 family that in humans is encoded by the IL1A gene.^[1]^[2] In general, Interleukin 1 is responsible for the production of inflammation, as well as the promotion of fever and sepsis. IL-1α inhibitors are being developed to interrupt those processes and treat diseases.

IL-1α is produced mainly by activated macrophages, as well as neutrophils, epithelial cells, and endothelial cells. It possesses metabolic, physiological, haematopoietic activities, and plays one of the central roles in the regulation of the immune responses. It binds to the interleukin-1 receptor.^[3]^[4] It is on the pathway that activates tumor necrosis factor-alpha.

Discovery

Interleukin 1 was discovered by Gery in 1972.^[5]^[6]^[7] He named it lymphocyte-activating factor (LAF) because it was a lymphocyte mitogen. It was not until 1985 that interleukin 1 was discovered to consist of two distinct proteins, now called interleukin-1 alpha and interleukin-1 beta.^[2]

Alternative names

IL-1α is also known as fibroblast-activating factor (FAF), lymphocyte-activating factor (LAF), B-cell-activating factor (BAF), leukocyte endogenous mediator (LEM), epidermal cell-derived thymocyte-activating factor (ETAF), serum amyloid A inducer or hepatocyte-stimulating factor (HSP), catabolin, hemopoetin-1 (H-1), endogenous pyrogen (EP), and proteolysis-inducing factor (PIF).

Synthesis and structure

IL-1α is a unique member in the cytokine family in the sense that the structure of its initially synthesized precursor does not contain a signal peptide fragment (same is known for IL-1β and IL-18). After processing by the removal of N-terminal amino acids by specific proteases, the resulting peptide is called "mature" form. Calpain, a calcium-activated cysteine protease, associated with the plasma membrane, is primarily responsible for the cleavage of the IL-1α precursor into a mature molecule.^[8] Both the 31kDa precursor form of IL-1α and its 18kDa mature form are biologically active.

The 31 kDa IL-1α precursor is synthesized in association with cytoskeletal structures (microtubules), unlike most secreted proteins, which are translated on ribosomes associated with rough endoplasmic reticulum.

The three-dimensional structure of the IL-1α contains an open-ended barrel composed entirely of beta-pleated strands. Crystal structure analysis of the mature form of IL-1α shows that it has two sites of binding to IL-1 receptor. There is a primary binding site^[9] located at the open top of its barrel, which is similar but not identical to that of IL-1β.

Production and cellular sources

IL-1α is constitutively produced by epithelial cells. It is found in substantial amounts in normal human epidermis and is distributed in a 1:1 ratio between living epidermal cells and stratum corneum.^[9]^[10]^[11] The constitutive production of large amounts of IL-1α precursor by healthy epidermal keratinocytes interfere with the important role of IL-1α in immune responses, assuming skin as a barrier, which prevents the entry of pathogenic microorganisms into the body.

The essential role of IL-1α in maintenance of skin barrier function, especially with increasing age,^[12] is an additional explanation of IL-1α constitutive production in epidermis.

With the exception of skin keratinocytes, some epithelial cells and certain cells in central nervous system, the mRNA coding for IL-1α (and, thus, IL-1α itself) is not observed in health in most of cell types, tissues, and blood, in spite of wide physiological, metabolic, haematopoietic, and immunological IL-1α activities.

A wide variety of other cells only upon stimulation can be induced to transcribe the IL-1α genes and produce the precursor form of IL-1α,^[13] Among them are fibroblasts, macrophages, granulocytes, eosinophils, mast cells and basophils, endothelial cells, platelets, monocytes and myeloid cell lines, blood T-lymphocytes and B-lymphocytes, astrocytes, kidney mesangial cells, Langerhans cells, dermal dendritic cells, natural killer cells, large granular lymphocytes, microglia, blood neutrophils, lymph node cells, maternal placental cells and several other cell types.

IL1A is found on the surface of senescent cells, where it contributes to the production of senescence-associated secretory phenotype (SASP) factors.^[14]

These data suggest that IL-1α is normally an epidermal cytokine.

Interactions

IL1A has been shown to interact with HAX1,^[15] and NDN.^[16]

Although there are many interactions of IL-1α with other cytokines, the most consistent and most clinically relevant is its synergism with TNF. IL-1α and TNF are both acute-phase cytokines that act to promote fever and inflammation. There are, in fact, few examples in which the synergism between IL-1α and TNFα has not been demonstrated. These include radioprotection, the Shwartzman reaction, PGE2 synthesis, sickness behavior, nitric oxide production, nerve growth factor synthesis, insulin resistance, loss of mean body mass, and IL-8 and chemokine synthesis.^[17]

Translation of mRNA for IL1A is highly dependent upon mTOR activity.^[18] IL1A and NF-κB mutually induce each other in a positive feedback loop.^[19]^[14]

Regulatory molecules

The most important regulatory molecule for IL-1α activity is IL-1Ra, which is usually produced in a 10- to 100-fold molar excess.^[20] In addition, the soluble form of the IL-1R type I has a high affinity for IL-1α and is produced in a 5-10 molar excess. IL-10 also inhibits IL-1α synthesis.^[21]

Biological activity

In vitro

IL-1α possesses biological effect on cells in the picomolar to femtomolar range. In particular, IL-1α:

stimulates keratinocytes and macrophages for induced IL-1α secretion
induces pro-collagen type I and III synthesis
causes proliferation of fibroblasts, induces collagenase secretion, induces cytoskeletal rearrangements, induces IL-6 and GCSF secretion
induces cycloxygenase synthesis and prostaglandin PGE2 release
causes phosphorylation of heat shock protein
causes proliferation of smooth muscle cells, keratinocytes and stimulates release of other cytokines by keratinocytes
induces TNFα release by endothelial cells and Ca2+ release from osteoclasts.
stimulates hepatocytes for secretion of acute-phase proteins
induces proliferation of CD4+ cells, IL-2 production, co-stimulates CD8+/IL-1R+ cells, induces proliferation of mature B-cells and immunoglobulin secretion
kills a limited number of tumor cells types

In vivo

Shortly after an onset of an infection into organism, IL-1α activates a set of immune system response processes. In particular, IL-1α:

stimulates fibroblasts proliferation
induces synthesis of proteases, subsequent muscle proteolysis, release of all types of amino acids in blood and stimulates acute-phase proteins synthesis
changes the metallic ion content of blood plasma by increasing copper and decreasing zinc and iron concentration in blood
induces production of SASP factors by senescent cells as a result of mTOR activity^[18]^[19]
increases blood neutrophils
activates lymphocyte proliferation and induces fever

Topically administered IL-1α also stimulates expression of FGF and EGF, and subsequent fibroblasts and keratinocytes proliferation. This, plus the presence of large depot of IL-1α precursor in keratinocytes, suggests that locally released IL-1α may play an important role and accelerate wound healing.

IL-1α is known to protect against lethal doses of γ-irradiation in mice,^[22]^[23] possibly as a result of hemopoietin-1 activity.^[24]

Applications

Pharmaceutical

Clinical trials on IL-1α have been carried out that are specifically designed to mimic the protective studies in animals.^[17] IL-1α has been administered to patients during receiving autologous bone marrow transplantation.^[25] The treatment with 50 ng/kg IL-1α from day zero of autologous bone marrow or stem cells transfer resulted in an earlier recovery of thrombocytopenia compared with historical controls. IL-1α is currently being evaluated in clinical trials as a potential therapeutic in oncology indications.^[26]

An anti-IL-1α therapeutic antibody, MABp1, is being tested in clinical trials for anti-neoplastic activity in solid tumors.^[27] Blocking the activity of IL-1α has the potential to treat skin diseases such as acne.^[28]

References

Шаблон:Reflist

External links

Шаблон:MeshName

Шаблон:NLM content Шаблон:PDB Gallery Шаблон:Interleukins Шаблон:Interleukin receptor modulators

pl:Interleukina 1

[pmid8188271-1] Шаблон:Cite journal

[pmid2989698-2] 2,0 ^2,1 Шаблон:Cite journal

[pmid8699924-3] Шаблон:Cite journal

[pmid9208877-4] Шаблон:Cite journal

[pmid5033417-5] Шаблон:Cite journal

[pmid5033418-6] Шаблон:Cite journal

[pmid4549027-7] Шаблон:Cite journal

[pmid7893968-8] Шаблон:Cite journal

[pmid3007615-9] 9,0 ^9,1 Шаблон:Cite journal

[pmid2997285-10] Шаблон:Cite journal

[pmid3486328-11] Шаблон:Cite journal

[pmid15009713-12] Шаблон:Cite journal

[isbn0-12-252673-2a-13] Шаблон:Cite book

[pmid26147250-14] 14,0 ^14,1 Шаблон:Cite journal

[pmid11554782-15] Шаблон:Cite journal

[pmid12913118-16] Шаблон:Cite journal

[isbn0-12-252673-2b-17] 17,0 ^17,1 Шаблон:Cite book

[pmid28167236-18] 18,0 ^18,1 Шаблон:Cite journal

[pmid28371119-19] 19,0 ^19,1 Шаблон:Cite journal

[pmid9597123-20] Шаблон:Cite journal

[pmid8386517-21] Шаблон:Cite journal

[pmid3512714-22] Шаблон:Cite journal

[pmid2654945-23] Шаблон:Cite journal

[pmid1995530-24] Шаблон:Cite journal

[pmid8437596-25] Шаблон:Cite journal

[26] Шаблон:Cite journal

[pmid25484055-27] Шаблон:Cite journal

[pmid24890096-28] Шаблон:Cite journal

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

Партнерские ресурсы
Криптовалюты	Обмен криптовалют - www.bestchange.ru Криптовалютная биржа CoinEx Криптовалютная биржа Binance HIVE OS - операционная система для майнинга e4pool - Мультивалютный пул для майнинга.
Магазины	AliExpress — глобальная виртуальная (в Интернете) торговая площадка, предоставляющая возможность покупать товары производителей из КНР; computeruniverse.net - Интернет-магазин компьютеров(Промо код 5 Евро на первую покупку:FWWC3ZKQ);
Хостинг	DigitalOcean - американский провайдер облачных инфраструктур, с главным офисом в Нью-Йорке и с центрами обработки данных по всему миру;
Разное	Викиум - Онлайн-тренажер для мозга Like Центр - Центр поддержки и развития предпринимательства. Gamersbay - лучший магазин по бустингу для World of Warcraft. Ноотропы OmniMind N°1 - Усиливает мозговую активность. Повышает мотивацию. Улучшает память. Санкт-Петербургская школа телевидения - это федеральная сеть образовательных центров, которая имеет филиалы в 37 городах России. Lingualeo.com — интерактивный онлайн-сервис для изучения и практики английского языка в увлекательной игровой форме. Junyschool (Джунискул) – международная школа программирования и дизайна для детей и подростков от 5 до 17 лет, где ученики осваивают компьютерную грамотность, развивают алгоритмическое и креативное мышление, изучают основы программирования и компьютерной графики, создают собственные проекты: игры, сайты, программы, приложения, анимации, 3D-модели, монтируют видео. Умназия - Интерактивные онлайн-курсы и тренажеры для развития мышления детей 6-13 лет SkillBox - это один из лидеров российского рынка онлайн-образования. Среди партнеров Skillbox ведущий разработчик сервисного дизайна AIC, медиа-компания Yoola, первое и самое крупное русскоязычное аналитическое агентство Tagline, онлайн-школа дизайна и иллюстрации Bang! Bang! Education, оператор PR-рынка PACO, студия рисования Draw&Go, агентство performance-маркетинга Ingate, scrum-студия Sibirix, имидж-лаборатория Персона. «Нетология» — это университет по подготовке и дополнительному обучению специалистов в области интернет-маркетинга, управления проектами и продуктами, дизайна, Data Science и разработки. В рамках Нетологии студенты получают ценные теоретические знания от лучших экспертов Рунета, выполняют практические задания на отработку полученных навыков, общаются с экспертами и единомышленниками. Познакомиться со всеми продуктами подробнее можно на сайте https://netology.ru, линейка курсов и профессий постоянно обновляется. StudyBay Brazil – это онлайн биржа для португалоговорящих студентов и авторов! Студент получает уникальную работу любого уровня сложности и больше свободного времени, в то время как у автора появляется дополнительный заработок и бесценный опыт. Автор24 — самая большая в России площадка по написанию учебных работ: контрольные и курсовые работы, дипломы, рефераты, решение задач, отчеты по практике, а так же любой другой вид работы. Сервис сотрудничает с более 70 000 авторов. Более 1 000 000 работ уже выполнено. StudyBay – это онлайн биржа для англоязычных студентов и авторов! Студент получает уникальную работу любого уровня сложности и больше свободного времени, в то время как у автора появляется дополнительный заработок и бесценный опыт.

Английская Википедия:Interleukin 1-alpha

Содержание