Disease relevance of IL1A

• Identification of an IL1A gene segment that determines aberrant constitutive expression of interleukin-1 alpha in systemic sclerosis [1].
• Eleven SNPs show some evidence of association with ESRD, with the strongest associations in two IL1A variants, one SNP, rs1516792-3, in intron 5 (p=0.0015) and a 4-bp insertion/deletion within the 3'UTR, rs16347-2 (p=0.0024), among African Americans with non-T2DM-associated ESRD [2].
• CONCLUSION: We investigated interleukin polymorphisms in ovarian cancer but did not find any association between common polymorphisms of IL1A, IL1B, and IL1RN and the occurrence of ovarian cancer [3].
• Analysis of IL6 and IL1A gene polymorphisms in UK and Dutch patients with sarcoidosis [4].
• Association analysis of IL1A and IL1B variants in alopecia areata [5].

Psychiatry related information on IL1A

• We investigated the association of the interleukin 1alpha (IL1A) (-889) C/T polymorphism with Alzheimer's disease (AD) and with the extent of AD histopathological lesions, the senile/neuritic plaques (SPs/NPs) and neurofibrillary tangles [6].
• Association of IL-1 RN*2 allele and methionine synthase 2756 AA genotype with dementia severity of sporadic Alzheimer's disease [7].
• The systemic effects of IL-1 include fever, increased circulating neutrophils, hepatic acute phase proteins, slow wave sleep, elevated insulin levels and hypotension [8].
• Interleukin 1 (IL-1) plays an important role in host defense mechanisms by increasing body temperature, inducing the synthesis of a variety of lymphokines and hepatic acute phase proteins and acting as a chemoattractant for lymphocytes [9].
• We therefore investigated in healthy women the relationship between alexithymia and circulating levels of IL-1, IL-2 and IL-4 [10].

High impact information on IL1A

• Studies in the early to mid 1980s demonstrated that monocyte-derived or recombinant interleukin-1 (IL-1) causes secretion of hormones of the hypothalamic-pituitary-adrenal (HPA) axis, establishing that immunoregulators, known as cytokines, play a pivotal role in this bidirectional communication between the immune and neuroendocrine systems [11].
• We found and replicated association between asthma and the D2S308 microsatellite, 800 kb distal to the IL1 cluster on 2q14 [12].
• Activation of the transcription factor NF-kappaB by tumor necrosis factor (TNF) and interleukin-1 (IL-1) requires the NF-kappaB-inducing kinase (NIK) [13].
• An IL-1-stimulated protein kinase cascade resulting in phosphorylation of the small heat shock protein hsp27 has been identified in KB cells [14].
• Twenty weeks after the end of supplementation, the production of IL-1 beta, IL-1 alpha, and tumor necrosis factor had returned to the presupplement level [15].

Chemical compound and disease context of IL1A

• However, delaying the initial IL-1ra treatment 3 hours after the induction of colitis (total 6 doses) was effective in reducing inflammatory index (by 60%), MPO activity (by 79%), PGE2 (by 62%), and LTB4 (by 72%) whereas colonic IL-1 alpha levels were unchanged compared with vehicle-treated animals [16].
• Incubation with different stimuli (lipopolysaccharide [LPS], phytohemagglutinin [PHA], Staphylococcus epidermidis, or IL-1 alpha) resulted in production of IL-6 [17].
• The levels of IL-1 and TNF produced in vitro peaked at 24 hours of culture and correlated with stage and the presence (or absence) of extensive osteolytic bone disease [18].
• One hour after the start of the 30-min IL-1 infusion, which caused mild cardiovascular toxicity, plasma levels of IL-6 reached a peak of 25 +/- 9 ng/L (mean +/- SEM), IL-8 reached a peak of 311 +/- 100 ng/L at 2 h, and nitrite/nitrate peaked after 10 h to 89 +/- 27 mumol/L [19].
• These results suggest that: (1) IL-1 and TNF stimulate bone resorption in part by increasing osteoclast formation and (2) an extremely low concentration of these factors can synergistically increase osteoclast formation in the absence of other factors, such as 1,25-(OH)2D3 [20].

Biological context of IL1A

• CONCLUSION: These findings suggest that a DNA binding protein containing the Ets domain is constitutively expressed only in fibroblasts from the affected skin of SSc patients and regulates the transcription of the IL1A gene, which contributes to the fibrogenic phenotype of fibroblasts in SSc [1].
• CONCLUSION: Our observations suggest that the CTG haplotype of the IL1A gene may be an important marker for the susceptibility to, and the severity of, SSc [21].
• The DNA protein binding activity for the cis-element of the IL1A gene was determined by electrophoretic mobility shift assay (EMSA) [1].
• RESULTS: We confirmed the presence of 2 SNPs at positions -889 (C/T) and +4845 (G/T) of the IL1A gene, as previously reported [21].
• A reporter construct (pLuc.-1437) was prepared that contained a 1.5-kb genomic fragment extending from -1437 to +39 relative to the transcription start site of the IL1A gene inserted upstream of the luciferase gene [1].

Anatomical context of IL1A

• RESULTS: Affected fibroblasts exhibited a strong nuclear run-on signal, indicative of constitutive transcription activity of the IL1A gene [1].
• IL-1 treatment of endothelial cell monolayers for 4 hours induced a four- to eight-fold increase in adhesion for each cell type [22].
• Regulation of cytokine production in the human thymus: epidermal growth factor and transforming growth factor alpha regulate mRNA levels of interleukin 1 alpha (IL-1 alpha), IL-1 beta, and IL-6 in human thymic epithelial cells at a post-transcriptional level [23].
• IL-1ra competed for binding of 125I-IL-1 alpha to type I IL-1R present on EL-4 thymoma cells, 3T3 fibroblasts, hepatocytes, and Chinese hamster ovary cells expressing recombinant mouse type I IL-1R [24].
• Anti-IL-1 antiserum blocked the induction of smooth muscle cell IL-1 gene expression by rIL-1 beta [25].

Associations of IL1A with chemical compounds

• RESULTS: Control of plasma viraemia could be predicted from carriage of allele 2 at position -889 in the IL1A gene (IL1A-889*2) [26].
• IL-1ra and 35F5 also blocked PMN accumulation after intraperitoneal injection of lipopolysaccharide or proteose peptone, suggesting IL-1 is important in mediating responses to these agents [24].
• Native human IL-1 beta and IL-1 alpha stimulated prostaglandin E2 secretion by human embryonic lung fibroblasts at half-maximal concentrations of 3 +/- 1.2 pM (+/- SEM) and 10 +/- 2.3 pM, respectively [27].
• Polymyxin B did not prevent IL-1-induced IL-1 expression by these cells, but blocked the effect of endotoxin [25].
• CONCLUSIONS: Bacterial cell wall polymers stimulate IL-1 and IL-1ra expression in vivo and in vitro [28].

Physical interactions of IL1A

• IL-1ra competitively inhibits binding of both IL-1 alpha and IL-1 beta to cell surface receptors without inducing any discernible intracellular responses [29].
• Cell-associated IL-1, particularly IL-1 alpha and membrane-bound TNF alpha, can also play a crucial role in the process of cell-cell interaction [30].
• By contrast, the initial translation product of IL-1 alpha mRNA can bind to the IL-1 receptor without further proteolytic processing [31].
• However, after a 2-day LDL incubation, NF-kappa B binding could be induced by over 63% with a very low dose of IL-1 alpha [32].
• Internalization at 37 degrees C demonstrated that only 19% of IL-1 beta was internalized and that binding with IL-1 alpha was entirely cell surface [33].

Regulatory relationships of IL1A

• IL-1 beta mRNA is detected by Northern blot analysis in old fibroblasts and its expression is further enhanced by a treatment with IL-1 alpha [34].
• Coincident with this synergistic induction of myeloid CSFs, treatment of CDCL cells with IL-1 alpha induces a 300% increase in the expression of TNF receptors [35].
• Recombinant IL-1 alpha-induced proliferation was partially inhibited by anti-IL-6 antibody [36].
• In contrast, IFN-gamma suppressed mRNA accumulation for IL-beta after stimulation with IL-1 alpha by 60 to 95% [37].
• IL-4 expression in human T cells is selectively inhibited by IL-1 alpha and IL-1 beta [38].

Other interactions of IL1A

• Two distinct but distantly related complementary DNAs encoding proteins sharing human interleukin-1 (IL-1) activity (termed IL-1 alpha and IL-1 beta), were isolated from a macrophage cDNA library [39].
• Second, sCD23 triggers the release of other inflammatory mediators such as IL-1 alpha, IL-1 beta, and IL-6 [40].
• The ratio of IL-1ra to IL-1 alpha proteins was significantly increased in involved psoriatic skin compared with normal skin [41].
• IL-1 alpha induction of TNF receptors reaches a peak after 6 hours and gradually returns to baseline level by 24 hours [35].
• Colony formation of both lines was uninfluenced by IL1 alpha or IL-3 [42].

Analytical, diagnostic and therapeutic context of IL1A

• Surprisingly, the IL1A genotype distribution was markedly different in control subjects with positive (ie, >/=1 positive reaction) and negative skin test responses (P =.006) [43].
• IL1RN, IL1A and IL1B genotypes were determined using restriction-enzyme analysis [44].
• The administration of IL-1ra blocks the effects of IL-1 in some animal models of septic shock, inflammatory arthritis, graft-versus-host disease, and inflammatory bowel disease [29].
• While neither IL-1ra nor 35F5 had intrinsic activity in bioassays using T helper D10.G4.1 cells and mouse thymocytes, both agents blocked the ability of IL-1 to stimulate proliferation of these cells [24].
• S1 nuclease protection assays demonstrated that primary leukemic ATL cells from five out of six patients, as well as one patient with T4+ chronic lymphocytic leukemia, contained considerable quantities of IL-1 beta messenger RNA (mRNA) and small amounts of IL-1 alpha mRNA [45].

References