Tumor Cell-Associated IL-1α Affects Breast Cancer Progression and Metastasis in Mice through Manipulation of the Tumor Immune Microenvironment.

IL-1α is a dual function cytokine that affects inflammatory and immune responses and plays a pivotal role in cancer. The effects of intracellular IL-1α on the development of triple negative breast cancer (TNBC) in mice were assessed using the CRISPR/Cas9 system to suppress IL-1α expression in 4T1 breast cancer cells. Knockout of IL-1α in 4T1 cells modified expression of multiple genes, including downregulation of cytokines and chemokines involved in the recruitment of tumor-associated pro-inflammatory cells. Orthotopical injection of IL-1α knockout (KO) 4T1 cells into BALB/c mice led to a significant decrease in local tumor growth and lung metastases, compared to injection of wild-type 4T1 (4T1/WT) cells. Neutrophils and myeloid-derived suppressor cells were abundant in tumors developing after injection of 4T1/WT cells, whereas more antigen-presenting cells were observed in the tumor microenvironment after injection of IL-1α KO 4T1 cells. This switch correlated with increased infiltration of CD3+CD8+ and NKp46+cells. Engraftment of IL-1α knockout 4T1 cells into immunodeficient NOD.SCID mice resulted in more rapid tumor growth, with increased lung metastasis in comparison to engraftment of 4T1/WT cells. Our results suggest that tumor-associated IL-1α is involved in TNBC progression in mice by modulating the interplay between immunosuppressive pro-inflammatory cells vs. antigen-presenting and cytotoxic cells.

Comparison between hangeshashinto and dexamethasone for IL-1α and ß-defensin 1 production by human oral keratinocytes.

OBJECTIVE: Human ß-defensin 1 (hBD-1) is a antimicrobial peptide that is constantly secreted by oral tissues. Hangeshashinto (HST), a traditional Japanese medicine, has been reported to be effective against stomatitis. This study aimed to clarify the profile of HST by comparing the system of production of interleukin-1α (IL-1α) and hBD-1 in human oral mucosal epithelial cells with dexamethasone (DEX), a steroid used for the treatment of stomatitis. METHODS: Human oral keratinocytes (HOK) were treated with HST, DEX, or HST components (baicalein, baicalin, berberine, and glycyrrhizin) for 24 h, and subsequently cultured for 24 h with or without Pam3CSK4 or lipopolysaccharide (LPS). The cell supernatants, total RNA, and intracellular proteins were collected, and changes in IL-1α and hBD-1 protein production and gene expression were evaluated using ELISA and RT-PCR. The phosphorylation of NF-kB and the cell proliferative ability of HOK were evaluated by western blotting and XTT assay, respectively. RESULTS: DEX (0.01-10 µM) significantly suppressed IL-1α and hBD-1 production induced by either Pam3CSK4 or LPS, and also decreased cell growth. In contrast, HST inhibited Pam3CSK4- and LPS-induced IL-1α production at a concentration range of 12.5-100 µg/mL without affecting the cell proliferative capacity and hBD-1 production of HOK. Baicalein and baicalin, which are flavonoid ingredients of HST, showed anti-IL-1α production. CONCLUSION: HST may be useful as a therapeutic agent for stomatitis and other inflammatory diseases of the oral cavity.

Thrombin-activated interleukin-1α drives atherogenesis, but also promotes vascular smooth muscle cell proliferation and collagen production.

AIMS: Atherosclerosis is driven by multiple processes across multiple body systems. For example, the innate immune system drives both atherogenesis and plaque rupture via inflammation, while coronary artery-occluding thrombi formed by the coagulation system cause myocardial infarction and death. However, the interplay between these systems during atherogenesis is understudied. We recently showed that coagulation and immunity are fundamentally linked by the activation of interleukin-1α (IL-1α) by thrombin, and generated a novel knock-in mouse in which thrombin cannot activate endogenous IL-1α [IL-1α thrombin mutant (IL-1αTM)]. METHODS AND RESULTS: Here, we show significantly reduced atherosclerotic plaque formation in IL-1αTM/Apoe-/- mice compared with Apoe-/- and reduced T-cell infiltration. However, IL-1αTM/Apoe-/- plaques have reduced vascular smooth muscle cells, collagen, and fibrous caps, indicative of a more unstable phenotype. Interestingly, the reduced atherogenesis seen with thrombin inhibition was absent in IL-1αTM/Apoe-/- mice, suggesting that thrombin inhibitors can affect atherosclerosis via reduced IL-1α activation. Finally, bone marrow chimeras show that thrombin-activated IL-1α is derived from both vessel wall and myeloid cells. CONCLUSIONS: Together, we reveal that the atherogenic effect of ongoing coagulation is, in part, mediated via thrombin cleavage of IL-1α. This not only highlights the importance of interplay between systems during disease and the potential for therapeutically targeting IL-1α and/or thrombin, but also forewarns that IL-1 may have a role in plaque stabilization.

Gene deletion of Interleukin-1α reduces ER stress-induced CHOP expression in macrophages and attenuates the progression of atherosclerosis in apoE-deficient mice.

The pathophysiology of atherosclerosis initiation and progression involves many inflammatory cytokines, one of them is interleukin (IL)-1α that has been shown to be secreted by activated macrophages. We have previously shown that IL-1α from bone marrow-derived cells is critical for early atherosclerosis development in mice. It is known that endoplasmic reticulum (ER) stress in macrophages is involved in progression to more advanced atherosclerosis, but it is still unknown whether this effect is mediated through cytokine activation or secretion. We previously demonstrated that IL-1α is required in ER stress-induced activation of inflammatory cytokines in hepatocytes and in the associated induction of steatohepatitis. In the current study, we aimed to examine the potential role of IL-1α in ER stress-induced activation of macrophages, which is relevant to progression of atherosclerosis. First, we demonstrated that IL-1α is required for atherosclerosis development and progression in the apoE knockout (KO) mouse model of atherosclerosis. Next, we showed that ER stress in mouse macrophages results in the protein production and secretion of IL-1α in a dose-dependent manner, and that IL-1α is required in ER stress-induced production of the C/EBP homologous protein (CHOP), a critical step in ER stress-mediated apoptosis. We further demonstrated that IL-1α-dependent CHOP production in macrophages is specifically mediated through the PERK-ATF4 signaling pathway. Altogether, these findings highlight IL-1α as a potential target for prevention and treatment of atherosclerotic cardiovascular disease.

SOX9 and IL1A as the Potential Gene Biomarkers of the Oral Cancer.

OBJECTIVE: Oral cancer is one of the most common malignant tumors in the head and neck. It is easy to relapse, and the prognosis is poor. However, the molecular mechanism in the development of oral cancer is still unclear. METHODS: A total of 30 normal individuals and 30 patients with head and neck cancer who underwent surgery were recruited in the Fourth Hospital of Hebei Medical University between February 2019 and November 2021. Furthermore, Human Protein Atlas (HPA) analysis, RT-qPCR, and immunofluorescence were used to verify the expression of SOX9 and IL1A. The GSE69002 dataset was downloaded from the Gene Expression Omnibus (GEO) database. GEO2R was used to identify the differentially expressed genes (DEGs). The Protein-Protein Interaction (PPI) network was constructed by using the STRING, and Cytoscape software was performed for visualization. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for enrichment analysis were made via the DAVID, Metascape, Gene Set Enrichment Analysis (GSEA), and Bin Gene Ontology (BINGO) analysis. Gene Expression Profiling Interactive Analysis (GEPIA) analysis was used to analyze the expression level of hub genes and pathological stage. The cBioPortal can be used for mutation analysis and pathway prediction of hub genes. Kaplan Meier Plotter was used for survival analysis of hub genes. RESULTS: The relative expression level of SOX9 (P=0.021, t=4.332) and IL1A (P=0.011, t= -4.213) in oral cancer was significantly higher than that in the standard group (P<0.05). The DEGs are mainly enriched in cell division, inflammation, interleukin-12 beta-subunit binding, and interleukin- 10 receptor binding. All the differentially expressed gene pathways eventually converge in cell growth and apoptosis. No relationship between the pathologic stage and the expression of hub genes. The poor overall survival of patients with the high expression of SOX9 (Hazard Ratio (HR) = 1.46, P = 0.009) and IL1A (HR = 1.49, P = 0.008). There were strong correlations between the hub genes and the head and neck neoplasms via the Comparative Toxicogenomics Database (CTD). The immunofluorescence and PCR results showed that the level of SOX9 (P<0.001, t = -23.368) in the cancer group was significantly higher than that in the normal group; The level of IL1A in the cancer group was significantly higher than that in the normal group (P<0.001, t = -11.960). CONCLUSION: SOX9 and IL1A genes are highly expressed in oral cancer and might be potential therapeutic targets for oral cancer. The poor overall survival of patients with the high expression of SOX9 and IL1A.

Determining distinct roles of IL-1α through generation of an IL-1α knockout mouse with no defect in IL-1ß expression.

Interleukin 1α (IL-1α) and IL-1ß are the founding members of the IL-1 cytokine family, and these innate immune inflammatory mediators are critically important in health and disease. Early studies on these molecules suggested that their expression was interdependent, with an initial genetic model of IL-1α depletion, the IL-1α KO mouse (Il1a-KOline1), showing reduced IL-1ß expression. However, studies using this line in models of infection and inflammation resulted in contrasting observations. To overcome the limitations of this genetic model, we have generated and characterized a new line of IL-1α KO mice (Il1a-KOline2) using CRISPR-Cas9 technology. In contrast to cells from Il1a-KOline1, where IL-1ß expression was drastically reduced, bone marrow-derived macrophages (BMDMs) from Il1a-KOline2 mice showed normal induction and activation of IL-1ß. Additionally, Il1a-KOline2 BMDMs showed normal inflammasome activation and IL-1ß expression in response to multiple innate immune triggers, including both pathogen-associated molecular patterns and pathogens. Moreover, using Il1a-KOline2 cells, we confirmed that IL-1α, independent of IL-1ß, is critical for the expression of the neutrophil chemoattractant KC/CXCL1. Overall, we report the generation of a new line of IL-1α KO mice and confirm functions for IL-1α independent of IL-1ß. Future studies on the unique functions of IL-1α and IL-1ß using these mice will be critical to identify new roles for these molecules in health and disease and develop therapeutic strategies.

IL-1 Superfamily Member (IL-1A, IL-1B and IL-18) Genetic Variants Influence Susceptibility and Clinical Course of Mediterranean Spotter Fever.

Mediterranean Spotted Fever (MSF) is one of the most common spotted fever Rickettsioses. Most cases of MSF follow a benign course, with a minority of cases being fatal. The severity of the infection depends on bacterial virulence, dose and host factors such as effective immune response and genetic background. Herein, we reported data on typing by competitive allele-specific PCR of functionally relevant polymorphisms of genes coding for MyD88 adapter-like (Mal/TIRAP) protein (rs8177374), interleukin(IL)-1 cluster (IL-1A rs1800587, IL-1B rs16944 and rs1143634) and IL-18 (rs187238), which might be crucial for an efficient immune response. The results enlighten the role that IL-1 gene cluster variants might play in susceptibility against Rickettsia conorii infection. In particular, the IL-1A rs1800587TT genotype was significantly increased in patients alone and combined in a haplotype composed by minor alleles rs1800587T, rs16944A and rs1143634A. This result was confirmed using the decision tree heuristic approach. Using this methodology, IL-1A rs1800587TT genotype was the better discrimination key among MSF patients and controls. In addition, the IL-1 gene cluster SNP genotypes containing minor alleles and IL-18 rs187238G positive genotypes were found as associated with risk of severe complications such as sepsis, septic shock, acute respiratory distress syndrome and coma. In conclusion, these data suggest that the evaluation of IL-1A, IL-1B and IL-18 gene SNPs can add useful information on the clinical course of patients affected by Mediterranean Spotted Fever, even if further confirmatory studies will be necessary.

Gene locus polymorphisms and expression levels of interleukin-1 in lumbar disc disease: A MOOSE-compliant meta-analysis and immunohistochemical study.

OBJECTIVE: To investigate the association between interleukin (IL)-1α (rs1800587), IL-1ß (rs1143634) and IL-1 receptor antagonist (RN) variable number tandem repeat polymorphisms, expression levels and lumbar disc disease (LDD). METHODS: All relevant articles were searched from 4 databases including PubMed, Embase, Web of Science and China National Knowledge Infrastructure. Odds ratios (OR) with 95% confidence intervals (CI) were calculated to evaluate the association between IL-1 gene locus polymorphisms (rs1800587 in IL-1α, rs1143634 in IL-1ß, variable number tandem repeat in interleukin-1 receptor antagonist) and LDD susceptibility. Statistical analysis was conducted by Review Manager (Revman) 5.31 software (Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Denmark). Furthermore, qRT-PCR and immunohistochemistry were performed to evaluate IL-1α, IL-1ß and interleukin-1 receptor antagonist expressions in the normal and degenerated disc. RESULTS: A total of 15 case-control studies (1455 cases and 2362 controls) were included in our meta-analysis. The pooled results suggested that IL-1α rs1800587 polymorphism was associated with an increased risk of LDD in overall population (T vs. C, OR = 1.21, 95% CI = 1.04-1.40, P = .01). The subgroup analysis found a significant association between IL-1ß rs1143634 polymorphism and LDD in Asian population (T vs. C, OR = 0.61, 95% CI = 0.39-0.96, P = .03). Results of qRT-PCR and immunohistochemistry demonstrated that expressions of IL-1α and IL-1ß were significantly increased in the degenerated disc. (all P < .05). CONCLUSION: IL-1α rs1800587 and IL-1ß rs1143634 polymorphisms were significantly associated with LDD in overall population and in Asian population, respectively. The increased expression levels of IL-1α and IL-1ß may be the important risk factors for LDD.

Genetic and Pharmacological Disruption of Interleukin-1α Leads to Augmented Murine Aortic Aneurysm.

BACKGROUND: Interleukin-1 (IL-1) signaling has an established role as a cytokine signaling pathway important for progression of abdominal aortic aneurysms (AAAs). While the IL-1ß ligand and IL-1R1 have been previously investigated, the role of the IL-1α ligand in AAAs remains unknown. In this study, we sought to examine the role of IL-1α in AAAs using genetic and pharmacologic approaches. METHODS: Eight-week-old wild-type (WT) or IL-1α knock-out (KO) male and female mice (n = 10-16/group) underwent experimental AAA and were harvested 14 days following surgery to assess AAA size and characteristics. In separate studies, 8-week-old WT mice were treated with an inhibitor to IL-1α during AAA formation and harvested 14 days following surgery. Finally, WT and IL-1α KO mice were administered Anakinra, an IL-R1 inhibitor, during AAA formation to determine the effect of inhibiting IL-1R1 when IL-1α is knocked out. RESULTS: Male and female IL-1α KO mice had larger AAAs compared to WT AAAs (male: 153% vs. 89.2%, P = 0.0001; female: 86.6% vs. 63.5%, P = 0.02). IL-1α KO mice had greater elastin breakage (P = 0.01), increased levels of macrophage staining (P = 0.0045), and greater pro-metallo proteinase 2 (P = 0.02). Pharmacologic inhibition of WT male mice with an IL-1α neutralizing antibody resulted in larger AAAs (133.1% vs. 77.0%, P < 0.001). Finally, treatment of IL-1α KO male mice with Anakinra decreased AAA formation compared with vehicle control AAAs (Anakinra + IL-1α KO: 47.7% vs. WT: 147.1%; P = 0.0001). CONCLUSIONS: IL-1α disruption using either genetic or pharmacologic approaches worsens AAAs.

Five Variable Number of Tandem Repeats Loci (D17S5, APOB, TPO Intron 10, IL-1α Intron 6, and CIAS1) in Thais and Application in the Prenatal Diagnostic Laboratory.

Background: Prenatal diagnosis of genetic disease requires DNA analysis of fetal tissue of a responsible gene. Accurate diagnosis is useful for the appropriate management of pregnancy. However, maternal contamination of fetal specimens poses a high preanalytical risk of prenatal misdiagnosis. We have examined five variable number of tandem repeat (VNTR) polymorphisms for use in monitoring potential maternal contamination. Materials and Methods: A study was conducted to examine the heterozygosities of five VNTR loci including, D17S5, APOB, TPO intron 10, IL-1α intron 6, and CIAS1 in 200 unrelated Thai subjects and applied to the monitoring of maternal contamination in 22 families at risk of having fetuses with severe thalassemia. Results: The heterozygosities of D17S5, APOB, TPO intron 10, IL-1α intron 6, and CIAS1 VNTRs were 59.5, 19.5, 66.0, 35.5, and 42.0%, respectively. Therefore, the TPO intron 10 and D17S5 loci were chosen for prenatal diagnosis of thalassemia in 22 families. Analyses of these VNTRs demonstrated an increase of informative data from 59.1% provided by the routine D1S80 VNTR analysis to 90.9%. Conclusions: The VNTR diagnostic procedure described above is simple, cost-effective, rapid, and does not require the use of sophisticated instruments; it should prove useful in the prenatal diagnosis of thalassemia.

Genome-wide association study of primary dysmenorrhea in the Taiwan Biobank validates associations near the NGF and IL1 gene loci.

Using the Taiwan Biobank, we aimed to identify traits and genetic variations that could predispose Han Chinese women to primary dysmenorrhea. Cases of primary dysmenorrhea included those who self-reported "frequent dysmenorrhea" in a dysmenorrhea-related Taiwan Biobank questionnaire, and those who have been diagnosed with severe dysmenorrhea by a physician. Controls were those without self-reported dysmenorrhea. Customized Axiom-Taiwan Biobank Array Plates were used to perform whole-genome genotyping, PLINK was used to perform association tests, and HaploReg was used to conduct functional annotations of SNPs and bioinformatic analyses. The GWAS analysis included 1186 cases and 24,020 controls. We identified 53 SNPs that achieved genome-wide significance (P < 5 × 10-8, which clustered in 2 regions. The first SNP cluster was on chromosome 1, and included 24 high LD (R2 > 0.88) variants around the NGF gene (lowest P value of 3.83 × 10-13 for rs2982742). Most SNPs occurred within NGF introns, and were predicted to alter regulatory binding motifs. The second SNP cluster was on chromosome 2, including 7 high LD (R2 > 0.94) variants around the IL1A and IL1B loci (lowest P value of 7.43 × 10-10 for rs11676014) and 22 SNPs that did not reach significance after conditional analysis. Most of these SNPs resided within IL1A and IL1B introns, while 2 SNPs may be in the promoter histone marks or promoter flanking regions of IL1B. To conclude, data from this study suggest that NGF, IL1A, and IL1B may be involved in the pathogenesis of primary dysmenorrhea in the Han Chinese in Taiwan.

Nonredundancy of IL-1α and IL-1ß is defined by distinct regulation of tissues orchestrating resistance versus tolerance to infection.

Interleukin-1α (IL-1α) and IL-1ß are inflammatory cytokines with important roles in health and disease. They trigger the same receptor and elicit comparable cellular responses but, for poorly understood reasons, are not redundant in vivo. Here, we decoupled IL-1α and IL-1ß functions that drive protective responses against invasive infection with group A Streptococcus. IL-1ß was essential for pathogen clearance, hence resistance to infection, by inducing granulocyte colony-stimulating factor at the infection site and establishing emergency granulopoiesis. In contrast, IL-1α governed reprogramming of liver metabolic pathways associated with tolerance to infection. The IL-1α-dominated hepatic regulation corresponded to high IL-1α levels in the liver during infection. Conversely, IL-1ß was critical for the regulation of the spleen transcriptome, which correlated with ample IL-1ß expression in this tissue. The results identify distinct and organ-specific roles of IL-1α versus IL-1ß and implicate spatial restriction of their expression and bioavailability during infection as the underlying mechanism.

The interactions between interleukin-1 family genes: IL1A, IL1B, IL1RN, and obesity parameters.

BACKGROUND: Obesity has been recognized as a worldwide growing problem, producing many pathologies including the promotion of "proinflammatory state." The etiology of human obesity is still only partially understood; however, the genetic background has been proved. Its nature is complex, and currently, it appears that the combined effects of the interactions among multiple genes should receive more attention. Due to the fact that obesity promotes proinflammatory conditions, in this study, we investigated the genetic polymorphism of IL-1 family genes in healthy people with normal and elevated body mass index (BMI) and fat %. RESULTS: The single-nucleotide polymorphisms (SNPs) within the IL1A -889C > T (rs1800587), IL1B + 3954 T > C (rs1143634), and IL1RN -87G > A (rs2234677) genes alone were associated neither with BMI nor fat % values in tested group. The associations between SNP-SNP interaction and BMI for the IL1B × IL1RN interactions were significant for dominant model (p = 0.02) and codominant model (p = 0.03). The same SNP-SNP interaction (IL1B × IL1RN) was associated also with fat % for codominant (p = 0.01) and recessive (p = 0.002) models. CONCLUSIONS: This study further confirmed that IL-1 family genes are involved in genetic background of obesity. It has been shown that interaction IL1B × IL1RN was associated with both BMI and fat % with rare T allele protecting form higher values. Thus, even if certain polymorphisms in single genes of IL-1 family cannot be defined as related to obesity in examined population, the genetic interrelationships should be analyzed.

The impact of extractable organic matter from gasoline and alternative fuel emissions on bronchial cell models (BEAS-2B, MucilAir™).

Air pollution caused by road traffic has an unfavorable impact on the environment and also on human health. It has previously been shown, that complete gasoline emissions lead to toxic effects in cell models originating from human airways. Here we focused on extractable organic matter (EOM) from particulate matter, collected from gasoline emissions from fuels with different ethanol content. We performed cytotoxicity evaluation, quantification of mucin and extracellular reactive oxygen species (ROS) production, DNA breaks detection, and selected gene deregulation analysis, after one and five days of exposure of human bronchial epithelial model (BEAS-2B) and a 3D model of the human airway (MucilAir™). Our data suggest that the longer exposure had more pronounced effects on the parameters of cytotoxicity and mucin production, while the impacts on ROS generation and DNA integrity were limited. In both cell models the expression of CYP1A1 was induced, regardless of the exposure period or EOM tested. Several other genes, including FMO2, IL1A, or TNF, were deregulated depending on the exposure time. In conclusion, ethanol content in the fuels did not significantly impact the toxicity of EOM. Biological effects were mostly linked to xenobiotics metabolism and inflammatory response. BEAS-2B cells were more sensitive to the treatment.

Comparative proteomic analysis of nuclear and cytoplasmic compartments in human cardiac progenitor cells.

Clinical trials evaluating cardiac progenitor cells (CPC) demonstrated feasibility and safety, but no clear functional benefits. Therefore a deeper understanding of CPC biology is warranted to inform strategies capable to enhance their therapeutic potential. Here we have defined, using a label-free proteomic approach, the differential cytoplasmic and nuclear compartments of human CPC (hCPC). Global analysis of cytoplasmic repertoire in hCPC suggested an important hypoxia response capacity and active collagen metabolism. In addition, comparative analysis of the nuclear protein compartment identified a significant regulation of a small number of proteins in hCPC versus human mesenchymal stem cells (hMSC). Two proteins significantly upregulated in the hCPC nuclear compartment, IL1A and IMP3, showed also a parallel increase in mRNA expression in hCPC versus hMSC, and were studied further. IL1A, subjected to an important post-transcriptional regulation, was demonstrated to act as a dual-function cytokine with a plausible role in apoptosis regulation. The knockdown of the mRNA binding protein (IMP3) did not negatively impact hCPC viability, but reduced their proliferation and migration capacity. Analysis of a panel of putative candidate genes identified HMGA2 and PTPRF as IMP3 targets in hCPC. Therefore, they are potentially involved in hCPC proliferation/migration regulation.

IL-1A is associated with postoperative survival and immune contexture in clear cell renal cell carcinoma.

BACKGROUND: Interleukin-1α (IL-1α) is thought to play a major role in renal cell carcinoma (RCC), but the specific mechanism is unclear. In this study, we explored the potential mechanism of the role of IL-1α in RCC. METHODS: Two cohorts were included in this study: The Cancer Genome Atlas (TCGA) cohort (n=521) and Fudan University Shanghai Cancer Center (FUSCC) cohort (n=198). These cohorts were used for cell infiltration-related analyses. RESULTS: In TCGA cohort, expression of IL-1α was significantly increased in patients with RCC. High IL-1α mRNA expression and intratumoral IL-1α+ cells were correlated with poor OS, which remained significant after adjustment for confounders. Elevated IL-1α mRNA expression and increased intratumoral IL-1α+ cell infiltration were associated with less mast cell infiltration in RCC. Among the relationships between IL-1α and cytotoxic factors, IL-1α was correlated with IFN-γ, TNFSF11, and GZMA. Among the relationships between IL-1α and immunosuppressive factors, we found that IL-1α was correlated with PDCD1, CD274, CTL1A4, LAG3, and BTLA. CONCLUSION: Expression of IL-1α was significantly correlated with the prognosis of RCC patients. IL-1α may participate in the development and progression of renal cancer through interactions with immune infiltrating mast cells. Our data demonstrate that IL-1α is a prognostic factor and potential therapeutic target for RCC.

Bioinformatics and in-silico findings reveal medical features and pharmacological targets of biochanin A against colorectal cancer and COVID-19.

Severe mortality due to the COVID-19 pandemic resulted from the lack of effective treatment. Although COVID-19 vaccines are available, their side effects have become a challenge for clinical use in patients with chronic diseases, especially cancer patients. In the current report, we applied network pharmacology and systematic bioinformatics to explore the use of biochanin A in patients with colorectal cancer (CRC) and COVID-19 infection. Using the network pharmacology approach, we identified two clusters of genes involved in immune response (IL1A, IL2, and IL6R) and cell proliferation (CCND1, PPARG, and EGFR) mediated by biochanin A in CRC/COVID-19 condition. The functional analysis of these two gene clusters further illustrated the effects of biochanin A on interleukin-6 production and cytokine-cytokine receptor interaction in CRC/COVID-19 pathology. In addition, pathway analysis demonstrated the control of PI3K-Akt and JAK-STAT signaling pathways by biochanin A in the treatment of CRC/COVID-19. The findings of this study provide a therapeutic option for combination therapy against COVID-19 infection in CRC patients.

Association between common polymorphisms in IL-1 and TNFα and risk of peri-implant disease: A meta-analysis.

BACKGROUND: Pro-inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor α (TNFα) play important roles in host immune response and bone metabolism during dental implant osseointegration. Whether the functional polymorphisms in IL-1α, IL-1ß and TNFα were associated with peri-implant disease was unclear, and we performed the present meta-analysis for this purpose. METHODS: Eligible studies investigating IL-1α C-889T, IL-1ß C+3954T and C-511T, TNFα G-308A, composite genotype of IL-1α C-889T and IL-1ß C+3954T for association with peri-implant disease, including peri-implantitis (PI), marginal bone loss (MBL) and implant failure/loss (IF/IL), were searched on several literature databases prior to April 30, 2021. Odds ratio (OR) and corresponding 95% confidence interval (CI) were calculated for each polymorphism in different genetic models and for composite genotype comparing carriers to non-carriers. RESULTS: Twenty-seven studies (1324 cases with peri-implant disease and 1808 controls with healthy implants) were included. There was significant correlation between IL-1α C-889T and peri-implant disease in all genetic models. IL-1ß C+3954T was associated with peri-implant disease risk in allelic (OR = 1.66, 95%CI 1.17-2.35, p = 0.004) and dominant model (OR = 1.74, 95%CI 1.19-2.53, p = 0.004), and in subgroups of Asians, Caucasians, non-smokers, IF/IL and PI. TT genotype of IL-1ß C-511T increased the risk of peri-implant disease (OR = 1.68, 95%CI 1.15-2.43, p = 0.007) and MBL (OR = 4.33, 95%CI 1.72-10.9, p = 0.002) compared to CC+CT genotypes. We did not observed a significant association between TNFα G-308A and peri-implant diseases in overall or subgroups analysis. Carriers of positive composite genotype of IL-1α C-889T and IL-1ß C+3954T had 1.95-fold (95%CI 1.35-2.80, p<0.001) risk of peri-implant disease and 1.76-fold (95%CI 1.05-2.95, p = 0.032) risk of IF/IL than non-carriers. CONCLUSION: Functional polymorphisms of IL-1α (C-889T), IL-1ß (C+3954T, C-511T) and composite genotype of IL-1 can be used as predictive markers for peri-implant disease, whereas TNFα G-308A polymorphism was not associated with peri-implant disease.

The role of single nucleotide polymorphisms of IL-1A -889C>T (rs1800587), TNF-A -238G>A (rs361525), and VDR TaqI (rs731236) on susceptibility to herniated nucleus pulposus: a systematic review and meta-analysis.

Background: The objective of this study was to determine the role of single nucleotide polymorphisms (SNPs) in interleukin 1 alpha ( IL-1A), tumor necrosis factor-alpha ( TNF-A), and vitamin D receptor ( VDR) genes on the susceptibility to herniated nucleus pulposus (HNP). Methods: Four databases (PubMed, Embase, Cochrane, and Web of Science) were searched as of April 1 st, 2021. Authors, publication year, targeted genes, genotype and allele frequency in each case and control groups were collected. Newcastle-Ottawa scale was used to evaluate the publication quality. The pooled estimates of association of IL-1A -889C>T (rs1800587), TNF-A -238G>A (rs361525), and VDR TaqI (rs731236) and susceptibility to HNP were assessed using Z test and presented as odd ratio (OR) and 95% confidence intervals (95%CI). Results: We screened 3,067 unique studies for eligibility and three, two and nine studies on IL-1A -889C>T, TNF-A -238G>A, and VDR TaqI were included, respectively, in our meta-analysis. The studies consisting 369 HNP cases and 433 controls for IL-1A -889C>T, 252 cases and 259 controls for TNF-A -238G>A and 1130 cases and 2096 controls for VDR TaqI. Our pooled estimates indicated that there was no significant association of those SNPs with the susceptibility to HNP in any genotype, dominant model, recessive model, or allele comparations. Conclusion: Although individual studies suggested the important role of gene expression dysregulation associated with SNPs in IL-1A, TNF-A, and VDR, our data indicated that IL-1A -889C>T, TNF-A -238G>A, and VDR TaqI had weak association with HNP susceptibility in both genotypes and allele distributions. However, since heterogeneity was identified among studies included in this meta-analysis, further meta-analysis with a larger population and subgroup analysis on specific population are warranted to support this finding.

Early Inflammatory Cytokine Expression in Cerebrospinal Fluid of Patients with Spontaneous Intraventricular Hemorrhage.

We investigated cerebrospinal fluid (CSF) expression of inflammatory cytokines and their relationship with spontaneous intracerebral and intraventricular hemorrhage (ICH, IVH) and perihematomal edema (PHE) volumes in patients with acute IVH. Twenty-eight adults with IVH requiring external ventricular drainage for obstructive hydrocephalus had cerebrospinal fluid (CSF) collected for up to 10 days and had levels of interleukin-1α (IL-1α), IL-1ß, IL-6, IL-8, IL-10, tumor necrosis factor-α (TNFα), and C-C motif chemokine ligand CCL2 measured using enzyme-linked immunosorbent assay. Median [IQR] ICH and IVH volumes at baseline (T0) were 19.8 [5.8-48.8] and 14.3 [5.3-38] mL respectively. Mean levels of IL-1ß, IL-6, IL-10, TNF-α, and CCL2 peaked early compared to day 9-10 (p < 0.05) and decreased across subsequent time periods. Levels of IL-1ß, IL-6, IL-8, IL-10, and CCL2 had positive correlations with IVH volume at days 3-8 whereas positive correlations with ICH volume occurred earlier at day 1-2. Significant correlations were found with PHE volume for IL-6, IL-10 and CCL2 at day 1-2 and with relative PHE at days 7-8 or 9-10 for IL-1ß, IL-6, IL-8, and IL-10. Time trends of CSF cytokines support experimental data suggesting association of cerebral inflammatory responses with ICH/IVH severity. Pro-inflammatory markers are potential targets for injury reduction.