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Time course of mRNA expression specific for the IL-1α, IL-1β, COX-1, and COX-2 genes in whole brain after turpentine injection. Wild-type (+/+) or homozygous (−/−) mice were injected with 100 μl turpentine subcutaneously in the left hindlimb. Mice were killed at 0, 6, 12, and 24 h after turpentine injection, and poly A⁺ RNA was isolated from whole brain. Poly A⁺ RNA (5–10 μg) was electrophoresed on a denatured agarose gel and hybridized with specific probes. β-actin was used as a control. (A) IL-1α and IL-1β KO mice; (B) IL-1ra and IL-1α/β KO mice.
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Interleukin (IL)-1 is a major mediator of inflammation and exerts pleiotropic effects on the neuro-immuno-endocrine system. To elucidate pathophysiological roles of IL-1, we have first produced IL-1alpha/beta doubly deficient (KO) mice together with mice deficient in either the IL-1alpha, IL-1beta, or IL-1 receptor antagonist (IL-1ra) genes. These...
Citations
... IL-1 manifests many pleiotropic functions throughout the body as a lymphocyte-activating factor, in hemopoietin-1, osteoclast activation and secretion of metalloproteases, in fever development, and in maintaining homeostasis of the neuroimmuno-endocrine system. To prove this concept, Horai et al. [83] obtained and operated on KO mice carrying a null mutation in one of the IL-1α, IL-1β, or IL-1ra genes. The scientists concluded that all these forms of Il-1 work together in a regulatory milieu that controls fever development and glucocorticoid synthesis in normal physiology and under stress conditions. ...
Erythropoiesis is initiated with the transformation of multipotent hematopoietic stem cells into committed erythroid progenitor cells in the erythroblastic islands of the bone marrow in adults. These cells undergo several stages of differentiation, including erythroblast formation, normoblast formation, and finally, the expulsion of the nucleus to form mature red blood cells. The erythropoietin (EPO) pathway, which is activated by hypoxia, induces stimulation of the erythroid progenitor cells and the promotion of their proliferation and survival as well as maturation and hemoglobin synthesis. The regulation of erythropoiesis is a complex and dynamic interaction of a myriad of factors, such as transcription factors (GATA-1, STAT5), cytokines (IL-3, IL-6, IL-11), iron metabolism and cell cycle regulators. Multiple microRNAs are involved in erythropoiesis, mediating cell growth and development, regulating oxidative stress, erythrocyte maturation and differentiation, hemoglobin synthesis, transferrin function and iron homeostasis. This review aims to explore the physiology of steady-state erythropoiesis and to outline key mechanisms involved in ineffective erythropoiesis linked to anemia, chronic inflammation, stress, and hematological malignancies. Studying aberrations in erythropoiesis in various diseases allows a more in-depth understanding of the heterogeneity within erythroid populations and the development of gene therapies to treat hematological disorders.
... NSG (NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ) mice were from The Jackson Laboratory, Israel. IL-1α KO mice and IL-1Ra KO mice (BALB/c background) were generated, as described [86], and kindly provided by Yoichiro Iwakura, Tokyo University. IL-1α KO and IL-1Ra KO mice were housed under specific pathogen-free conditions at the animal facilities of the faculty of Health Sciences, Ben-Gurion University. ...
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.
... Tnfr2 −/− (Erickson et al., 1994), and Ccr2 gfp/gfp mice (Satpathy et al., 2013) were obtained from the Jackson Laboratory. Tnfr1 −/− (Pfeffer et al., 1993), Ripk1 K45A (Berger et al., 2014), Il1r1 −/− (Glaccum et al., 1997), Tlr4 −/− (Hoshino et al., 1999), Il1a −/− (Horai et al., 1998), Il1b −/− (Horai et al., 1998), and Il1a −/− Il1b −/− (Horai et al., 1998) mice were previously described. All mice were bred at the University of Pennsylvania by homozygous mating and housed separately by genotype. ...
... Tnfr2 −/− (Erickson et al., 1994), and Ccr2 gfp/gfp mice (Satpathy et al., 2013) were obtained from the Jackson Laboratory. Tnfr1 −/− (Pfeffer et al., 1993), Ripk1 K45A (Berger et al., 2014), Il1r1 −/− (Glaccum et al., 1997), Tlr4 −/− (Hoshino et al., 1999), Il1a −/− (Horai et al., 1998), Il1b −/− (Horai et al., 1998), and Il1a −/− Il1b −/− (Horai et al., 1998) mice were previously described. All mice were bred at the University of Pennsylvania by homozygous mating and housed separately by genotype. ...
... Tnfr2 −/− (Erickson et al., 1994), and Ccr2 gfp/gfp mice (Satpathy et al., 2013) were obtained from the Jackson Laboratory. Tnfr1 −/− (Pfeffer et al., 1993), Ripk1 K45A (Berger et al., 2014), Il1r1 −/− (Glaccum et al., 1997), Tlr4 −/− (Hoshino et al., 1999), Il1a −/− (Horai et al., 1998), Il1b −/− (Horai et al., 1998), and Il1a −/− Il1b −/− (Horai et al., 1998) mice were previously described. All mice were bred at the University of Pennsylvania by homozygous mating and housed separately by genotype. ...
Tumor necrosis factor (TNF) is a pleiotropic inflammatory cytokine that mediates antimicrobial defense and granuloma formation in response to infection by numerous pathogens. We previously reported that Yersinia pseudotuberculosis colonizes the intestinal mucosa and induces the recruitment of neutrophils and inflammatory monocytes into organized immune structures termed pyogranulomas (PG) that control Yersinia infection. Inflammatory monocytes are essential for the control and clearance of Yersinia within intestinal PG, but how monocytes mediate Yersinia restriction is poorly understood. Here, we demonstrate that TNF signaling in monocytes is required for bacterial containment following enteric Yersinia infection. We further show that monocyte-intrinsic TNFR1 signaling drives the production of monocyte-derived interleukin-1 (IL-1), which signals through IL-1 receptors on non-hematopoietic cells to enable PG-mediated control of intestinal Yersinia infection. Altogether, our work reveals a monocyte-intrinsic TNF-IL-1 collaborative inflammatory circuit that restricts intestinal Yersinia infection.
... WT, IL-1a/b (original breeding pairs from Yoichiro Iwakura, Tokyo University of Science, Japan) and P2X7R knockout mice (from Christopher Gabel, Pfizer) were bred and genotyped in the MGTU of IEM (Medical Gene Technology Unit of Institute of Experimental Medicine) as described in previous studies. 73,74 Animals were maintained on a 12:12 light-dark cycle in a temperature-(23 G 2 C) and humidity-controlled room (60 G 10%), with food and water ad libitum. Before and under the behavioral experiments, up to 5 adult littermates mice per cage were housed in standard mouse cages with corncob bedding (expect for residents in the resident intruder test). ...
Purinergic dysfunctions are associated with mania and depression pathogenesis. P2X7 receptor (P2X7R) mediates the IL-1β maturation via NLRP3 inflammasome activation. We tested in a mouse model of the subchronic amphetamine (AMPH)-induced hyperactivity whether P2X7R inhibition alleviated mania-like behavior through IL-1β.
Treatment with JNJ-47965567, a P2X7R antagonist, abolished AMPH-induced hyperlocomotion in wild-type and IL-1α/β-knockout male mice. The NLRP3 inhibitor MCC950 failed to reduce AMPH-induced locomotion in WT mice, whereas the IL-1 receptor antagonist anakinra slightly increased it. AMPH increased IL-10, TNF-α, and TBARS levels, but did not influence BDNF levels, serotonin, dopamine, and noradrenaline content in brain tissues in either genotypes. JNJ-47965567 and P2rx7-gene deficiency, but not IL-1α/β-gene deficiency, attenuated AMPH-induced [³H]dopamine release from striatal slices. In wild-type and IL-1α/β-knockout female mice, JNJ-47965567 was also effective in attenuating AMPH-induced hyperlocomotion.
This study suggests that AMPH-induced hyperactivity is modulated by P2X7Rs, but not through IL-1β.
... were produced and used in the study at 10 weeks of age. The IL-1β KO mice (Horai et al. 1998) were backcrossed C57BL/6msSlc having a congenicity of > 99.998 at the Institute of Medical Science, the University of Tokyo. At 6-8 weeks of age, the DNA was extracted from ear samples obtained from each mouse and analyzed by polymerase chain reaction (PCR) to confirm its genotype using primers (Lac Z GAG GTG CTG TTT CTG GTC TTC ACC , IL-1β common CAC ATA TCC AGC ACT CTG CTT TCA G, IL-1β W TGG TCA GTG TGT GGG TTG CCTT). ...
Acrylamide is an environmental electrophile that has been produced in large amounts for many years. There is concern about the adverse health effects of acrylamide exposure due to its widespread industrial use and also presence in commonly consumed foods and others. IL-1β is a key cytokine that protects the brain from inflammatory insults, but its role in acrylamide-induced neurotoxicity remains unknown. We reported recently that deletion of IL-1β gene exacerbates ACR-induced neurotoxicity in mice. The aim of this study was to identify genes or signaling pathway(s) involved in enhancement of ACR-induced neurotoxicity by IL-1β gene deletion or ACR-induced neurotoxicity to generate a hypothesis mechanism explaining ACR-induced neurotoxicity. C57BL/6 J wild-type and IL-1β KO mice were exposed to ACR at 0, 12.5, 25 mg/kg by oral gavage for 7 days/week for 4 weeks, followed by extraction of mRNA from mice cerebral cortex for RNA sequence analysis. IL-1β deletion altered the expression of genes involved in extracellular region, including upregulation of PFN1 gene related to amyotrophic lateral sclerosis and increased the expression of the opposite strand of IL-1β. Acrylamide exposure enhanced mitochondria oxidative phosphorylation, synapse and ribosome pathways, and activated various pathways of different neurodegenerative diseases, such as Alzheimer disease, Parkinson disease, Huntington disease, and prion disease. Protein network analysis suggested the involvement of different proteins in related to learning and cognitive function, such as Egr1, Egr2, Fos, Nr4a1, and Btg2. Our results identified possible pathways involved in IL-1β deletion-potentiated and ACR-induced neurotoxicity in mice.
... Female BALB/cA mice were purchased from CLEA Japan (Tokyo, Japan). IL-1KO mice (deficient in both IL-1α and IL-1β, BALB/c background) were obtained from Prof. Yoichiro Iwakura (Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Japan) (Horai et al., 1998). Mice were maintained at 22 ± 3°C with 50 ± 15% humidity and a 12 hr light/dark cycle in conventional conditions. ...
The hydrophilic compound 2-hydroxyethyl methacrylate (HEMA) is a major component of dental bonding materials, and it enhances the binding of resin-composites to biomolecules. However, HEMA is a well-known contact sensitizer. We reported previously that intradermal injection of HEMA induces the production of IL-1 locally in the skin. Keratinocytes are the first barrier against chemical insults and constitutively express IL-1α. In this study, we analyzed whether HEMA induces the production of inflammatory cytokines from murine keratinocyte cell line Pam212 cells. We demonstrated that HEMA induced the release of 17-kDa mature IL-1α and caused cytotoxicity. The activity of calpain, an IL-1α processing enzyme, was significantly higher in HEMA-treated cells. The thiol-containing antioxidant N-acetyl cysteine (NAC) inhibited HEMA-induced IL-1α release but not cytotoxicity. NAC inhibited intracellular calpain activity and reactive oxygen species (ROS) production induced by HEMA. NAC post-treatment also inhibited IL-1α release and intracellular ROS production induced by HEMA. Furthermore, HEMA-induced in vivo inflammation also inhibited by NAC. NAC inhibited polymerization of HEMA through adduct formation via sulfide bonds between the thiol group of NAC and the reactive double bond of HEMA. HEMA-induced IL-1α release and cytotoxicity were also inhibited if HEMA and NAC were pre-incubated before adding to the cells. These results suggested that NAC inhibited IL-1α release through decreases in intracellular ROS and the adduct formation with HEMA. We concluded that HEMA induces IL-1α release from skin keratinocytes, and NAC may be a promising candidate as a therapeutic agent against inflammation induced by HEMA.
... Certain growth factors stimulate anabolism, and proinflammatory cytokines activate catabolic pathways. IL-1 knockout mice exhibit normal growth [27]. After surgery to induce OA joints, IL-1β knockout mice show accelerated development of OA lesions in both operated and unoperated joints [28]. ...
We investigated the effects of the cytokine inhibitors IL-1 receptor antagonist (IL-1Ra) and soluble tumor necrosis factor receptor-1 (sTNFR1) on the extracellular matrix metabolism of human intervertebral discs (IVDs) and the roles of IL-1β and TNF in the homeostasis of IVD cells. The 1.2% alginate beads and the explants obtained from 35 human lumbar discs were treated with cytokine inhibitors. Extracellular matrix metabolism was evaluated by proteoglycan (PG) and collagen syntheses and IL-1β, TNF, and IL-6 expressions after three days of culture in the presence or absence of IL-1Ra, sTNFR1, and cycloheximide. Simultaneous treatment with IL-1Ra and sTNFR1 stimulated PG and collagen syntheses in the NP and AF cells and explants. The IL-1β concentration was significantly correlated to the relative increase in PG synthesis in AF explants after simultaneous cytokine inhibitor treatment. The relative increase in PG synthesis induced by simultaneous cytokine treatment was significantly higher in an advanced grade of MRI. Expressions of IL-1β and TNF were upregulated by each cytokine inhibitor, and simultaneous treatment suppressed IL-1β and TNF productions. In conclusion, IL-1Ra and sTNFR1 have the potential to increase PG and collagen synthesis in IVDs. IL-1β and TNF have a feedback pathway to maintain optimal expression, resulting in the control of homeostasis in IVD explants.
... ICR-SCID mice were purchased from Taconic Biosciences. Ccl8/12 KO mice 54 were gifted by Dr. Sabina Islam and Il1b KO mice 68 were gifted by Dr. Dmitry Shayakhmetov, and were both bred in our colony on C57BL/6J genetic background. Mice of both sexes in the age range of 8-16 weeks were used for experiments. ...
Glioblastoma (GBM), a highly lethal brain cancer, is notorious for immunosuppression, but the mechanisms remain unclear. Here, we documented a temporospatial patterning of tumor-associated myeloid cells (TAMs) corresponding to vascular changes during GBM progression. As tumor vessels transitioned from the initial dense regular network to later scant and engorged vasculature, TAMs shifted away from perivascular regions and trafficked to vascular-poor areas. This process was heavily influenced by the immunocompetence state of the host. Utilizing a sensitive fluorescent UnaG reporter to track tumor hypoxia, coupled with single-cell transcriptomics, we revealed that hypoxic niches attracted and sequestered TAMs and cytotoxic T lymphocytes (CTLs), where they were reprogrammed toward an immunosuppressive state. Mechanistically, we identified chemokine CCL8 and cytokine IL-1β as two hypoxic-niche factors critical for TAM trafficking and co-evolution of hypoxic zones into pseudopalisading patterns. Therefore, perturbation of TAM patterning in hypoxic zones may improve tumor control.
... B6.B4B6-Chuk <tm1Mpa> /Cgn (Chuk f/f ) and B6.B4B6-Ikbkb <tm2.1Mpa> /Cgn (Ikbkb f/f ) mice that carry conditional Chuk and Ikbkb alleles that are deleted upon Cre-recombinase expression [30,31], as well as Il1b tm1Yiw Il1b-deficient mice (Il1b−/−; MGI #215739631) [32] and Cpa3.Cre+/mast cell-deficient mice in which mast cells undergo Trp53-mediated apoptosis (Cpa3.Cre) [33] were described elsewhere and were kindly donated by their founders. All mice used for these studies were originated from or back-crossed > F12 generations to the C57BL/6 background. ...
... We next analyzed TCGA pan-cancer transcriptome data to discover that IL1B mRNA levels were elevated in KRAS MUT and amplified cancers, and performed IL-1β immunohistochemistry in our own patients with resected LUAD [13] to find increased IL-1β protein expression in KRAS MUT LUAD compared with KRAS-wild-type ( WT ) LUAD and adjacent lung tissues ( Figure 1C,D). We next injected C57BL/6 mice competent (WT) and diploinsufficient for Il1b alleles (Il1b−/−) [32] with syngeneic cancer cell lines carrying Kras WT and Kras MUT alleles [10,11]. Both subcutaneous (s.c.) and pleural routes of tumor cell injection were employed, since we previously identified that malignant pleural effusions (MPE) in mice are exclusively elicited by Kras MUT tumor cells [10,11]. ...
... Differential gene expression (∆GE) analyses (GEO datasets GSE94847, GSE94880, GSE130624, and GSE130716; total n = 32) identified 13 BMDMspecific transcripts that were further induced by incubation with tumor-conditioned media (∆GE > 5; ANOVA p < 0.05) and included Il1b but not Il6 and Tnf reported elsewhere [57] ( Figure 3G and Table S1). In addition, NGL mice diploinsufficient in Il1b alleles [32] were resistant to tumor-induced NF-κB activation ( Figure 3H). Incubation of BMDM with Kras MUT tumor-conditioned media promoted their differentiation as assessed by flow cytometry for markers MHCII and CD206, and Il1b mRNA and IL-1β protein expression ( Figure 3I-L). ...
Simple Summary
Kirsten rat sarcoma virus (KRAS)-mutant cancers are frequent, metastatic, lethal, and largely undruggable. The aim of this study was to investigate the pathways through which KRAS-mutant cancers foster their growth, thereby unravelling novel therapeutic targets. We show that KRAS-mutant tumors secrete the protein versican, which then drives the activation of NF-κB kinase (IKK) β in a type of host immune cells called macrophages. Following this activation, macrophages fuel the tumor with interleukin (IL)-1β, to close an inflammatory loop through which KRAS-mutant cancers attract host immune cells to the tumor site to accelerate tumor growth and aggressiveness. Importantly, we show that targeting IL-1β and/or versican can be an effective treatment for KRAS-mutant cancers, holding great promise for cancer patients.
Abstract
Kirsten rat sarcoma virus (KRAS)-mutant cancers are frequent, metastatic, lethal, and largely undruggable. While interleukin (IL)-1β and nuclear factor (NF)-κB inhibition hold promise against cancer, untargeted treatments are not effective. Here, we show that human KRAS-mutant cancers are addicted to IL-1β via inflammatory versican signaling to macrophage inhibitor of NF-κB kinase (IKK) β. Human pan-cancer and experimental NF-κB reporter, transcriptome, and proteome screens reveal that KRAS-mutant tumors trigger macrophage IKKβ activation and IL-1β release via secretory versican. Tumor-specific versican silencing and macrophage-restricted IKKβ deletion prevents myeloid NF-κB activation and metastasis. Versican and IKKβ are mutually addicted and/or overexpressed in human cancers and possess diagnostic and prognostic power. Non-oncogene KRAS/IL-1β addiction is abolished by IL-1β and TLR1/2 inhibition, indicating cardinal and actionable roles for versican and IKKβ in metastasis.
... Experiments were performed on female and male IL-1 αβ gene-deficient KO mice backcrossed for 7-8 generations to C57Bl/6 mice. C57Bl/6 mice were used as wildtype (WT) controls, and the original breeding pairs were purchased from Charles River Ltd.(Wilmington, MA, USA) IL-1 αβ KO mice were generated at the University of Budapest, Institute of Experimental Medicine, as previously described [93]. We have not observed any remarkable differences in global IL-1α/β KO mice as compared to their WTs regarding their development, growth, general health, lifespan and fertility, which is well supported by the literature data [94,95]. ...
Chronic stress causes several pain conditions including fibromyalgia. Its pathophysiological mechanisms are unknown, and the therapy is unresolved. Since the involvement of interleukin-1 (IL-1) has been described in stress and inflammatory pain but no data are available regarding stress-induced pain, we studied its role in a chronic restraint stress (CRS) mouse model. Female and male C57Bl/6J wild-type (WT) and IL-1αβ-deficient (knock-out: IL-1 KO) mice were exposed to 6 h of immobilization/day for 4 weeks. Mechanonociception, cold tolerance, behavioral alterations, relative thymus/adrenal gland weights, microglia ionized calcium-binding adaptor molecule 1 (IBA1) and astrocyte glial fibrillary acidic protein (GFAP) integrated density, number and morphological transformation in pain-related brain regions were determined. CRS induced 15–20% mechanical hyperalgesia after 2 weeks in WT mice in both sexes, which was significantly reduced in female but not in male IL-1 KOs. Increased IBA1+ integrated density in the central nucleus of amygdala, primary somatosensory cortex hind limb representation part, hippocampus cornu ammonis area 3 (CA3) and periaqueductal gray matter (PAG) was present, accompanied by a cell number increase in IBA1+ microglia in stressed female WTs but not in IL-1 KOs. CRS induced morphological changes of GFAP+ astrocytes in WT but not in KO mice. Stress evoked cold hypersensitivity in the stressed animals. Anxiety and depression-like behaviors, thymus and adrenal gland weight changes were detectable in all groups after 2 but not 4 weeks of CRS due to adaptation. Thus, IL-1 mediates chronic stress-induced hyperalgesia in female mice, without other major behavioral alterations, suggesting the analgesic potentials of IL-1 in blocking drugs in stress-related pain syndromes.
