The liver responds to inflammation by down-regulating key hepatic genes involved in regulation of metabolic processes in the liver. This leads to disruption of drug metabolism and clearance and can cause drugs to become potentially ineffective or even toxic. To understand the mechanism of alteration of hepatic drug metabolism in inflammation, we are focusing on elucidating inflammation-induced signaling pathways in the liver. Cross-talk between the signaling components and DME gene regulators contribute to the down-regulation of these genes. We find that the LTA-mediated regulation of hepatic DME genes and serum cytokines involves the LTA receptor TLR2 as expected. However, the first adaptor protein, TIRAP, mediates the effects of LTA on DME genes in vivo and in isolated primary hepatocytes but not on cytokine expression in the liver.. In the liver, cytokines released from Kupffer cells bind to their respective receptors on hepatocytes to initiate signaling events, leading to down-regulation of ...
p>The checksum is a form of redundancy check that is calculated from the sequence. It is useful for tracking sequence updates.,/p> ,p>It should be noted that while, in theory, two different sequences could have the same checksum value, the likelihood that this would happen is extremely low.,/p> ,p>However UniProtKB may contain entries with identical sequences in case of multiple genes (paralogs).,/p> ,p>The checksum is computed as the sequence 64-bit Cyclic Redundancy Check value (CRC64) using the generator polynomial: x,sup>64,/sup> + x,sup>4,/sup> + x,sup>3,/sup> + x + 1. The algorithm is described in the ISO 3309 standard. ,/p> ,p class="publication">Press W.H., Flannery B.P., Teukolsky S.A. and Vetterling W.T.,br /> ,strong>Cyclic redundancy and other checksums,/strong>,br /> ,a href="http://www.nrbook.com/b/bookcpdf.php">Numerical recipes in C 2nd ed., pp896-902, Cambridge University Press (1993),/a>),/p> Checksum:i ...
Acts as a negative regulator of the Toll-like and IL-1R receptor signaling pathways. Attenuates the recruitment of receptor-proximal signaling components to the TLR4 receptor, probably through an TIR-TIR domain interaction with TLR4. Through its extracellular domain interferes with the heterodimerization of Il1R1 and IL1RAP.
The IUPHAR/BPS Guide to Pharmacology. Interleukin-4 receptor type I - IL-2 receptor family. Detailed annotation on the structure, function, physiology, pharmacology and clinical relevance of drug targets.
CD200 (OX2) is a broadly distributed cell surface glycoprotein that interacts with a structurally related receptor (CD200R) expressed on rodent myeloid cells and is involved in regulation of macrophage function. We report the first characterization of human CD200R (hCD200R) and define its binding characteristics to hCD200. We also report the identification of a closely related gene to hCD200R, designated hCD200RLa, and four mouse CD200R-related genes (termed mCD200RLa-d). CD200, CD200R, and CD200R-related genes were closely linked in humans and mice, suggesting that these genes arose by gene duplication. The distributions of the receptor genes were determined by quantitative RT-PCR, and protein expression was confirmed by a set of novel mAbs. The distribution of mouse and human CD200R was similar, with strongest labeling of macrophages and neutrophils, but also other leukocytes, including monocytes, mast cells, and T lymphocytes. Two mCD200 receptor-like family members, designated mCD200RLa and
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Apoptbsis plays critical roles in mammalian biology including embryonic development, cellular homeostasis and immune regulation. Genetic mutations or abnormal e...
Rabbit anti Human interleukin-1R accessory protein antibody recognizes IL-IL-1RAcP (IL-1 receptor accessory protein), an essential protein
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TLR signaling is mediated by the recruitment of distinct combinations of adaptor molecules to the cytoplasmic TIR domain of each TLR. Distribution and localization of the adaptor molecules are important factors controlling TLR-mediated signaling. TIRAP/Mal was found to be associated with the plasma membrane via a phosphatidylinositol 4,5-biphosphate-binding domain and facilitates MyD88 delivery to activated TLR4 (22). Also, myristoylation of TICAM-2/TRAM targets it to the plasma membrane and the Golgi apparatus, where it colocalizes with TLR4 (23). Thus, the role of these adaptor proteins other than TICAM-1 has been clearly demonstrated; TIRAP/Mal and TICAM-2/TRAM mainly function as bridges between TLR4 and the signaling adaptors, whereas MyD88 restricts its localization by TIRAP to assemble signal molecules around the TLR4 complex (9, 10, 24, 25). In this study we demonstrated that TICAM-1/TRIF delivers a signal in a unique fashion distinct from that of MyD88.. This is the first study to ...
The Toll/interleukin-1 receptor/resistance protein (TIR) domain is a protein-protein interaction domain consisting of 125-200 residues, widely distributed in animals, plants and bacteria but absent from fungi, archea and viruses. In plants and animals, these domains are found in proteins with functions in innate immune pathways, while in bacteria, some TIR domain-containing proteins interfere with the innate immune pathways in the host. TIR domains function as protein scaffolds, mostly involving self-association and homotypic interactions with other TIR domains. In the last 15 years, the three-dimensional structures of TIR domains from several mammalian, plant and bacterial proteins have been reported. These structures, jointly with functional data including the identification of interacting proteins, have started to provide insight into the molecular basis of the assembly of animal and plant immune signaling complexes, and for host immunosuppression by bacterial pathogens. This review focuses ...
Induction of lymphopenia has been exploited therapeutically to improve immune responses to cancer therapies and vaccinations. Whereas IL-15 has well-established roles in stimulating lymphocyte responses after lymphodepletion, the mechanisms regulating these IL-15 responses are unclear. We report that cell surface IL-15 expression is upregulated during lymphopenia induced by total body irradiation (TBI), cyclophosphamide, or Thy1 Ab-mediated T cell depletion, as well as in RAG−/− mice; interestingly, the cellular profile of surface IL-15 expression is distinct in each model. In contrast, soluble IL-15 (sIL-15) complexes are upregulated only after TBI or αThy1 Ab. Analysis of cell-specific IL-15Rα conditional knockout mice revealed that macrophages and dendritic cells are important sources of sIL-15 complexes after TBI but provide minimal contribution in response to Thy1 Ab treatment. Unlike with TBI, induction of sIL-15 complexes by αThy1 Ab is sustained and only partially dependent on ...
Interleukin-33 (IL-33) is a recently identified member of the IL-1 family of cytokines whose other members include IL-1a/b, IL-1Ra and IL-18. Its receptor has been shown to be ST2, an IL-1 receptor family member that also acts as a negative regulator of TLR-IL-1R signaling and IL-1R accessory protein (IL-1RAcP). Receptor binding of IL-33 activates NF-kappaB and MAP kinases and induces the expression of TH2-associated cytokines such as IL-4, IL-5 and IL-6. Prolonged IL-33 treatment of mice led to the development of eosinophilia, splenomegaly, and severe pathological changes in mucosal organs such as lungs, esophagus and small intestine. Recent experiments have shown that IL-33 can also co-localize with heterochromatin and possesses transcriptional repressor activities, indicating that IL-33 may function as both a proinflammatory cytokine and an intracellular nuclear factor with transcriptional regulatory properties. Despite its predicted molecular weight, IL-33 will often run at higher molecular ...
CD124, a subunit of IL-4R, is a 140 kD transmembrane glycoprotein. It associates with either the common γ-chain (CD132) to form the type I IL-4R complex, which specifically binds IL-4, or with IL-13Ra1 to form the type II IL-4R heterodimeric complex, which binds and transduces signals from either IL
Chuang CF, Bargmann CI. A Toll-interleukin 1 repeat protein at the synapse specifies asymmetric odorant receptor expression via ASK1 MAPKKK signaling ...
Build: Sat Nov 17 23:53:08 EST 2018 (commit: a759bb7). National Center for Advancing Translational Sciences (NCATS), 6701 Democracy Boulevard, Bethesda MD 20892-4874 • 301-435-0888. ...
In a series of previous studies, it was shown that immunologic inhibition of tumor growth (immunosurveillance) could be undermined in several different tumor models by tumor-induced secretion of TGF-β1 and the inhibitory effect of this cytokine on tumor antigen-specific cytolytic T cells ( 2, 10- 13). Furthermore, it was shown that such counter-immunosurveillance was initiated by NKT cells that secrete IL-13 and thereby induce Gr-1 cells to produce TGF-β1 ( 1- 3, 13). These studies led to attempts to treat tumors by disarming counter-immunosurveillance. Although these included the use of antagonists that block the activity of either of the above cytokines, they did not include approaches that address key signaling mechanisms involved such as those mediating IL-13 induction of TGF-β1 because the latter were as yet poorly understood.. With regard to this latter point, previous studies showing that IL-13 signals via the type II IL-4R, a heterodimer of the IL-4Rα and IL-13Rα1 that responds to ...
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Background and purpose: The inflammatory cytokine interleukin-1 (IL-1) has profound actions in the brain causing neuronal cell death and exacerbating mind damage. barrier model was generated by co-culture of porcine mind microvascular endothelial cells with astrocytes. The mechanisms of transcellular transport of IL-1β and IL-1 receptor antagonist were characterized with this model using endocytosis inhibitors and IL-1 receptor-blocking antibodies. Important results: Transcellular IL-1β and IL-1 receptor DMH-1 antagonist transport was temperature-dependent and IL-1β was transferred with higher affinity than IL-1 receptor antagonist. IL-1β inhibited IL-1 receptor antagonist transport more potently than IL-1 receptor antagonist inhibited IL-1β transport. Transport of IL-1β and IL-1 receptor antagonist was not via adsorptive-mediated endocytosis although inhibition of microtubule assembly significantly attenuated transport of both cytokines. An antibody directed DMH-1 to the type II IL-1 ...
IRAP (Interleukin-1 Receptor Antagonist Protein) is an anti-inflammation therapy that is best for patients suffering from Osteoarthritis.
The CpG6 mutation replaces a glycine possibly located in the αE helix of TLR9 with an arginine, and results in a hypomorphic allele that fails to respond to CpG ODN stimulation. It is likely the substitution of a charged amino acid for a glycine at this position disrupts helical formation as the previous amino acid is also charged. Many of the α-helices and connecting loops of the TIR domain are predicted to participate in binding partner recognition, and their mutation is expected to abrogate specific binding interactions. TIR domains in TLRs, IL receptors and the adapters MyD88 and TIRAP contain 3 conserved boxes (boxes 1, 2 and 3) required for signaling, which form part of the βA-strand, BB loop and αE-helix, respectively (2;3). Computational docking of the TLR2 TIR domain with the TIR domain of the myeloid differentiation (MyD)-88 adaptor protein suggests that TIR domains can interact in two different modes, one of which is mediated by αE-helix interactions. Further studies of the ...
IRAK1 - IRAK1 (untagged)-Human interleukin-1 receptor-associated kinase 1 (IRAK1), transcript variant 1 available for purchase from OriGene - Your Gene Company.
To view the Protein page, either click on the protein links in the box to the left or the blue bar above the Proteins graphic ...
IRAK4兔多克隆抗体(ab109335)可与人样本反应并经WB, ICC/IF实验严格验证。中国75%以上现货,所有产品均提供质保服务,可通过电话、电邮或微信获得本地专属技术支持。
Thus, let-7 family miRNA may potentially provide novel targets for the sildenafil citrate 100mg pills development of therapeutic strategies against OS. A 54-year-old woman presented with acute pulmonary edema with intractable hypertension and a history of lower limb claudication. Type I and type II interferons upregulate functional type I interleukin-1 receptor in a human fibroblast cell line TIG-1. We found significant racial susceptibility to drug-induced QT prolongation in this large urban study of acute overdoses. Our results indicate that administration of carprofen prior to surgery was effective in improving peri-operative analgesia in dogs undergoing TPLO.. The fundamental mechanism proposed to explain surface-enhanced Raman scattering (SERS) relies on electromagnetic field enhancement at optical frequencies. Cross-validation of this model with other TBI populations is recommended. Single transpulmonary thermodilution in off-pump coronary artery bypass sildenafil citrate 100mg tab ...
Platelet-activating factor acetylhydrolase precursor (EC 3.1.1.47) (PAF acetylhydrolase) (PAF 2-acylhydrolase) (LDL-associated phospholipase A2) (LDL-PLA(2)) (2-acetyl-1-alkylglycerophosphocholine esterase) (1-alkyl-2-acetylglycerophosphocholine esterase) [Source:Uniprot/SWISSPROT;Acc:Q90678 ...
The IL-1 cytokine network in epidermal cells was studied in vitro, using the spontaneously transformed HaCAT human keratinocyte line. Intracellular (ic) IL-1 alpha and IL-1 receptor antagonist protein (IL-1Ra) following cell lysis were readily identified assayed using a capture ELISA; whereas in culture supernatants IL-1Ra was not detected, and IL-1 alpha was present at only very low levels. Confluent cultures of HaCAT cells were shown to provide optimal conditions for the study, since confluence increased the icIL-1Ra:IL-1 alpha ratio to a level as seen in vivo, which was independent of Ca2+ concentration in the culture medium. The IL-1Ra extracted from HaCAT cell lysates was functionally active, as demonstrated in the mouse thymocyte co-proliferation assay which could be blocked using a rabbit anti-IL-1Ra antibody. Transforming growth factor-beta (TGF-beta 1) stimulated a dose-dependent increase in HaCAT cell IL-1 alpha without changing IL-1Ra concentration, with a resultant reduction in the icIL-1Ra:
IL-1R antagonist (IL-1Ra) exists as three well-characterized isoforms. The 17-kDa secretory IL-1Ra (sIL-1Ra) and 18-kDa intracellular IL-1Ra (icIL-1RaI) arise by alternative transcription of the same IL-1Ra gene. The recently described 16-kDa intracellular IL-1Ra (icIL-1RaII) is formed by alternative translation initiation of sIL-1Ra mRNA. Transcription and translation of IL-1Ra isoforms were examined in LPS-stimulated human neutrophils and PBMC using RT-PCR, ELISA, and Western blot analysis. LPS stimulation of neutrophils resulted in elevated sIL-1Ra mRNA levels by 1 h, whereas icIL-1RaI mRNA remained undetectable through 22 h of culture. Extracellular glycosylated sIL-1Ra protein and intracellular icIL-1RaII were observed in LPS-stimulated neutrophils by 3 h of culture; no icIL-1RaI protein was detected by immunoblot. LPS stimulation of PBMC resulted in elevated sIL-1Ra mRNA levels by 1 h and detectable icIL-1RaI mRNA at 8 h of culture. LPS-stimulated PBMC demonstrated extracellular glycosylated sIL
to circumvent innate immunity was demonstrated (Cirl et al. 2008, Nature Medicine 14, 399-406). This involves a bacterial TIR domain-containing protein (Tcp) that is secreted by bacterial pathogens and inhibits Toll-like receptor (TLR) signalling. ,p, Toll-like receptors have a central role in innate immunity. They recognise molecules from microbial pathogens and trigger an immune response through a signalling domain called TIR. Bacterial Tcps contain a TIR domain that mimics the TIR domain of Toll-like receptors. TLR signalling is interrupted when MyD88, a downstream component of TLR signalling, binds to the TIR domain of a bacterial Tcp instead of to the TIR domain of a Toll-like receptor. This way, secreted Tcps impair the release of cytokines and, subsequently, prevent an inflammatory response. ,p, Our data show that bacterial Tcps or the TIR domains contained in Tcps can be used to modulate cytokine responses of innate immune cells as is desirable in the treatment of autoimmune diseases. ...
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Interleukin 1 beta (IL-1β) is a pro-inflammatory cytokine that is produced by monocytes, macrophages, and dendritic cells (DCs). IL-1β signals through the IL-1 receptor, type 1 (IL-1R1) to activate the myeloid differentiation primary response 88 (MYD88) signaling pathway, which contains the cytoplasmic Toll/IL-1 receptor (TIR) domain adapter. IL-1β and the independently regulated IL-1α protein have overlapping pro-inflammatory activities to induce adhesion molecule expression on epithelial cells, control fever induction, initiate rheumatoid arthritis, and promote septic shock.
TCPA_CRIGR (P18279 ), TCPA_DICDI (Q55BM4 ), TCPA_DROME (P12613 ), TCPA_ENCCU (Q8SSC9 ), TCPA_HUMAN (P17987 ), TCPA_MACFA (Q4R5G2 ), TCPA_MONDO (Q9XT06 ), TCPA_MOUSE (P11983 ), TCPA_PALPA (Q9W790 ), TCPA_RAT (P28480 ), TCPA_SCHMA (Q94757 ), TCPA_SCHPO (O94501 ), TCPA_TETPY (O15891 ), TCPA_YEAST (P12612 ), TCPB_ARATH (Q940P8 ), TCPB_BOVIN (Q3ZBH0 ), TCPB_CAEEL (P47207 ), TCPB_DICDI (Q54ES9 ), TCPB_HUMAN (P78371 ), TCPB_MACFA (Q4R6F8 ), TCPB_MESAU (P86245 ), TCPB_MOUSE (P80314 ), TCPB_RAT (Q5XIM9 ), TCPB_SCHPO (Q10147 ), TCPB_YEAST (P39076 ), TCPD_ARATH (Q9LV21 ), TCPD_ASHGO (Q75A36 ), TCPD_BOVIN (Q2T9X2 ), TCPD_CAEEL (P47208 ), TCPD_CANGA (Q6FQT2 ), TCPD_DEBHA (Q6BXF6 ), TCPD_DICDI (Q54CL2 ), TCPD_HUMAN (P50991 ), TCPD_KLULA (Q6CL82 ), TCPD_MOUSE (P80315 ), TCPD_OCHTR (Q9NB32 ), TCPD_PONAB (Q5R637 ), TCPD_RAT (Q7TPB1 ), TCPD_SCHPO (P50999 ), TCPD_TAKRU (P53451 ), TCPD_YARLI (Q6C100 ), TCPD_YEAST (P39078 ), TCPE1_AVESA (P40412 ), TCPE2_AVESA (P54411 ), TCPE_ARATH (O04450 ), TCPE_CAEEL (P47209 ), ...
Research Report on Global Cytokine Inhibitor Sales Market Report 2017. The Report includes market price, demand, trends, size, Share, Growth, Forecast, Analysis & Overview.
Complete information for IL2RA gene (Protein Coding), Interleukin 2 Receptor Subunit Alpha, including: function, proteins, disorders, pathways, orthologs, and expression. GeneCards - The Human Gene Compendium
Complete information for IL20RA gene (Protein Coding), Interleukin 20 Receptor Subunit Alpha, including: function, proteins, disorders, pathways, orthologs, and expression. GeneCards - The Human Gene Compendium
A small case series reflected the therapeutic potential of the interleukin (IL)-1 receptor antagonist anakinra in patients with severe COVID-19 who ha...
IL-17 receptorska familija se sastoji od pet, široko distribuiranih receptora koji su specifični za individualne ligande. U ovoj familiji receptora, IL-17R je najbolje opisan. IL-17R vezuje oba IL-17A i IL-17F, i on je izražen u više tkiva: vaskularne endotelijske ćelije, periferne T ćelije, B ćelijske loze, fibroblast, pluća, mijelo-monocitne ćelije, i stromalne ćelije koštane srži.[4][16][17]. IL-17RB, vezuje IL-17B i IL-17E.[4][17] On je izražen u bubrezima, pankreasu, jetri, mozgu, i crevima.[4] IL-17RC je izražen u prostati, hrskavici, bubrezima, jetri, srcu i mišićima. NJegov gen podleže alternativnom splajsovanju i proizvodi rastvorni receptor, u dodatku obliku receptora vezanom za ćelijsku membranu. U sličnom maniru, IL-17RD gen može podleći alternativnom splajsovanju da proizvede rastvorni receptor. Ova osobina možda omogućava ovim receptorima da inhibiraju stimulatorne efekte njihovih još-nedefinisanih liganda.[4][17] Najmanje opisan od ovih receptora je ...
Recombinant Human IL-10 (mammalian expressed, carrier-free) - IL-10 was first described as a cytokine that is produced by T helper 2 (Th2) cell clones.
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Nold-Petry CA, Lo CY, Rudloff I, Elgass KD, Li S, Gantier MP, Lotz-Havla AS, Gersting SW, Cho SX, Lao JC, Ellisdon AM, Rotter B, Azam T, Mangan NE, Rossello FJ, Whisstock JC, Bufler P, Garlanda C, Mantovani A, Dinarello CA, Nold MF. IL-37 requires the receptors IL-18Ra and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction. Nat Immunol. 2015 Apr; 16(4):354-65 ...
IRAK2 encodes the interleukin-1 receptor-associated kinase 2, one of two putative serine/threonine kinases that become associated with the interleukin-1 receptor (IL1R) upon stimulation. IRAK2 is reported to participate in the IL1-induced upregulation of NF-kappaB ...
Data Details Area 2362 Sq Km Literacy Rate 42.84% Total Population 111975 Total Male Population 57,604 Total Female Population 54,371
The IL-23 Bioassay is a biologically relevant MOA-based assay that can be used to measure the potency and stability of antibodies and other biologics designed to stimulate or inhibit interactions with the IL-23 receptor (IL-23R).
Humira outsold all other drugs in 2019 in terms of revenue as cytokine inhibitor medications earned their way to three of the first four spots on the pharmaceut
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Several studies indicate that local immunoregulation and associated cytokines have a putative role in the development of cancer. There is evidence that pro-inflammatory cytokines such as interleukin-1 (IL-1) are critically involved with tumour progression. IL-1 receptor antagonist (IL-1Ra) is known to down regulate and limit the inflammatory response. Therefore we attempted to examine the influence of the known polymorphism of the IL-1Ra gene on the development of human colorectal cancer (CRC). The study included 125 patients with CRC and 134 controls. Variable number tandem repeat (VNTR) polymorphism in intron 2 of the IL-Ra gene was analysed by the polymerase chain reaction method. There was a significant difference in genotype distribution between CRC patients and controls (P=0.025) and also in allelic frequencies (P=0.012). In detail the carriage rate of allele 3 in CRC patients was significantly increased compared with controls (P=0.007). We also found that the allelic distribution differs ...
TAK-242 (resatorvid), a small molecule specific inhibitor of Toll-like receptor (TLR) 4 signaling, inhibits the production of lipopolysaccharide-induced inflammatory mediators by binding to the intracellular domain of TLR4. Previously, Cys747 in TLR4 was identified as the binding site of TAK-242. However, the mechanism by which TAK-242 inhibits TLR4 signaling after binding to TLR4 remains unknown. The present study demonstrated, using coimmunoprecipitation, that TAK-242 interferes with protein-protein interactions between TLR4 and its adaptor molecules. Among ten different human TLRs, TAK-242 selectively bound to TLR4. The time course of the inhibitory effect of TAK-242 on inflammatory mediator production corresponded to that of the binding of TAK-242 to TLR4. TAK-242 inhibited the association of TLR4 with TIR domain-containing adaptor protein (TIRAP) or TRIF-related adaptor molecule (TRAM) in HEK293 cells overexpressing TLR4, MD-2 and TIRAP or TRAM, respectively. TAK-242 inhibited the ...
In the original report describing GAG [7], it was shown that GAG has anti-inflammatory effects in mice. However, the mechanism through which GAG elicits its immunomodulatory effects remained a question at that time. In the present study, we demonstrate that GAG induces its anti-inflammatory effects by inducing the potent anti-inflammatory cytokine IL-1 receptor antagonist.. IL-1Ra can inhibit the activation of the IL-1 pathway by binding to the IL-1R type 1 receptor and prevents recruitment of the IL-1R accessory protein that is required for signalling. It has been repeatedly shown that IL-1 is an essential proinflammatory cytokine of the innate immunity. A deficient IL-1 pathway is also detrimental for the host, since it is an important protective pathway required to fight infection [17]. Thus the IL-1 axis is a potent pro-inflammatory pathway that needs to be tightly regulated, and IL-1Ra is a crucial player in this regulation. Therefore, it is rather surprising that the role of IL-1Ra in ...
These data demonstrate icIL-1ra type I mRNA, sIL-1ra mRNA, and IL-1ra protein in human coronary arteries. IL-1ra protein colocalizes with IL-1β predominantly in the endothelium of these arteries, with less IL-1ra mRNA expression occurring in less-diseased DCM arteries. To our knowledge, this is the first documentation of IL-1ra expression by HCAECs. We also show only icIL-1ra type I mRNA expression in HUVECs and HCAECs stimulated in vitro with LPS/PMA or TGF-β. Previous reports have failed to detect IL-1ra mRNA in these cell types with the use of other stimuli and less sensitive detection methods, such as Northern blots,5 and there are no previous reports of immunohistochemistry for IL-1ra in human vessels. With the use of immunoprecipitation/Western blot techniques, our data also confirm that the expression of IL-1ra in HUVECs and HCAECs is intracellular. We have also demonstrated that the rare allele (IL-1RN *2/*2) of a VNTR polymorphism in the IL-1RN gene is associated with significantly ...