Interleukin 1-alpha
Interleukin-1 alpha(IL-1 alpha) also known ashematopoietin 1is acytokineof theinterleukin 1 familythat in humans is encoded by theIL1Agene.[5][6]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 activatedmacrophages,as well asneutrophils,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 theinterleukin-1 receptor.[7][8]It is on the pathway that activatestumor necrosis factor-alpha.
Discovery
[edit]Interleukin 1 was discovered by Gery in 1972.[9][10][11]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 andinterleukin-1 beta.[6]
Alternative names
[edit]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
[edit]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 andIL-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 cysteineprotease,associated with the plasma membrane, is primarily responsible for the cleavage of the IL-1α precursor into a mature molecule.[12]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 toIL-1 receptor.There is a primary binding site[13]located at the open top of its barrel, which is similar but not identical to that of IL-1β.
Production and cellular sources
[edit]IL-1α is constitutively produced byepithelial cells.It is found in substantial amounts in normal humanepidermisand is distributed in a 1:1 ratio between living epidermal cells andstratum corneum.[13][14][15]The constitutive production of large amounts of IL-1α precursor by healthy epidermalkeratinocytesinterfere with the important role of IL-1α in immune responses, assumingskinas a barrier, which prevents the entry ofpathogenicmicroorganismsinto the body.
The essential role of IL-1α in maintenance of skin barrier function, especially with increasing age,[16]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,[17]Among them arefibroblasts,macrophages,granulocytes,eosinophils,mast cellsandbasophils,endothelial cells,platelets,monocytesandmyeloid celllines, bloodT-lymphocytesandB-lymphocytes,astrocytes,kidneymesangial cells,Langerhans cells,dermaldendritic cells,natural killer cells,large granularlymphocytes,microglia,bloodneutrophils,lymph nodecells, maternalplacentalcells and several other cell types.
IL1A is found on the surface ofsenescent cells,where it contributes to the production ofsenescence-associated secretory phenotype(SASP) factors.[18]
These data suggest that IL-1α is normally an epidermal cytokine.
Interactions
[edit]IL1A has been shown tointeractwithHAX1,[19]andNDN.[20]
Although there are many interactions of IL-1α with other cytokines, the most consistent and most clinically relevant is its synergism withTNF.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 andTNFαhas not been demonstrated. These include radioprotection, the Shwartzman reaction,PGE2synthesis, sickness behavior,nitric oxideproduction,nerve growth factorsynthesis,insulinresistance, loss of mean body mass, andIL-8andchemokinesynthesis.[21]
Translation ofmRNAfor IL1A is highly dependent uponmTORactivity.[22]IL1A andNF-κBmutually induce each other in apositive feedback loop.[23][18]
Regulatory molecules
[edit]The most important regulatory molecule for IL-1α activity isIL-1Ra,which is usually produced in a 10- to 100-fold molar excess.[24]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-10also inhibits IL-1α synthesis.[25]
Biological activity
[edit]In vitro
[edit]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, inducescollagenasesecretion, inducescytoskeletalrearrangements, inducesIL-6andGCSFsecretion
- inducescycloxygenasesynthesis andprostaglandinPGE2release
- causesphosphorylationofheat shock protein
- causes proliferation ofsmooth muscle cells,keratinocytesand stimulates release of other cytokines by keratinocytes
- induces TNFα release byendothelial cellsand Ca2+ release fromosteoclasts.
- stimulates hepatocytes for secretion of acute-phase proteins
- induces proliferation ofCD4+ cells,IL-2production, co-stimulates CD8+/IL-1R+ cells, induces proliferation of matureB-cellsandimmunoglobulinsecretion
- kills a limited number oftumor cellstypes
In vivo
[edit]Shortly after an onset of aninfectioninto organism, IL-1α activates a set ofimmune systemresponse processes. In particular, IL-1α:
- stimulates fibroblasts proliferation
- induces synthesis ofproteases,subsequentmuscleproteolysis,release of all types ofamino acidsin blood and stimulatesacute-phase proteinssynthesis
- changes the metallic ion content ofblood plasmaby increasing copper and decreasing zinc and iron concentration in blood
- induces production ofSASPfactors bysenescent cellsas a result ofmTORactivity[22][23]
- increases bloodneutrophils
- activateslymphocyteproliferation and inducesfever
Topically administered IL-1α also stimulates expression ofFGFandEGF,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 acceleratewound healing.
IL-1α is known to protect against lethal doses ofγ-irradiationin mice,[26][27]possibly as a result ofhemopoietin-1 activity.[28]
Applications
[edit]Pharmaceutical
[edit]Clinical trials on IL-1α have been carried out that are specifically designed to mimic the protective studies in animals.[21]IL-1α has been administered to patients during receiving autologous bone marrow transplantation.[29]The treatment with 50 ng/kg IL-1α from day zero of autologous bone marrow or stem cells transfer resulted in an earlier recovery ofthrombocytopeniacompared with historical controls. IL-1α is currently being evaluated in clinical trials as a potential therapeutic in oncology indications.[30]
An anti-IL-1α therapeutic antibody, MABp1, is being tested in clinical trials for anti-neoplastic activity in solid tumors.[31]Blocking the activity of IL-1α has the potential to treat skin diseases such as acne.[32]
References
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Further reading
[edit]- Verweij CL, Bayley JP, Bakker A, Kaijzel EL (2002). "Allele specific regulation of cytokine genes: Monoallelic expression of the IL-lA gene".Allele specific regulation of cytokine genes: monoallelic expression of the IL-1A gene.Advances in Experimental Medicine and Biology. Vol. 495. pp. 129–39.doi:10.1007/978-1-4615-0685-0_17.ISBN978-0-306-46656-4.PMID11774556.
- Griffin WS, Mrak RE (August 2002)."Interleukin-1 in the genesis and progression of and risk for development of neuronal degeneration in Alzheimer's disease".Journal of Leukocyte Biology.72(2): 233–8.doi:10.1189/jlb.72.2.233.PMC3835694.PMID12149413.
- Arend WP (2003). "The balance between IL-1 and IL-1Ra in disease".Cytokine & Growth Factor Reviews.13(4–5): 323–40.doi:10.1016/S1359-6101(02)00020-5.PMID12220547.
- Copeland KF (Dec 2005). "Modulation of HIV-1 transcription by cytokines and chemokines".Mini Reviews in Medicinal Chemistry.5(12): 1093–101.doi:10.2174/138955705774933383.PMID16375755.
- Schmidt DR, Kao WJ (January 2007). "The interrelated role of fibronectin and interleukin-1 in biomaterial-modulated macrophage function".Biomaterials.28(3): 371–82.doi:10.1016/j.biomaterials.2006.08.041.PMID16978691.
- Huynh-Ba G, Lang NP, Tonetti MS, Salvi GE (April 2007). "The association of the composite IL-1 genotype with periodontitis progression and/or treatment outcomes: a systematic review".Journal of Clinical Periodontology.34(4): 305–17.doi:10.1111/j.1600-051X.2007.01055.x.PMID17378887.
External links
[edit]- IL1A+protein,+humanat the U.S. National Library of MedicineMedical Subject Headings(MeSH)
This article incorporates text from theUnited States National Library of Medicine,which is in thepublic domain.