Interleukin-1 Receptor Expression Research Articles

Human chorionic gonadotropin triggers angiogenesis via the modulation of endometrial cell receptivity to interleukin 1: a new mechanism underlying embryo-maternal crosstalk

Embryo implantation is orchestrated by embryonic and maternal signals. Secretion of interleukin 1 (IL1) in response to the receptive endometrium induces molecular changes that are essential for embryonic implantation. Our objective was to investigate whether human chorionic gonadotropin (hCG), a major embryonic signal, modulates endometrial stromal cell receptivity to IL1 and assess the impact on tissue remodeling and angiogenesis. Cell treatment with hCG and/or IL1 and assessment of cell receptivity to IL1 and angiogenesis in vitro. Expression of IL1 receptors and angiogenic factors was analyzed by ELISA and qRT-PCR. Endothelial cell proliferation was evaluated using 3H-thimidine incorporation into DNA. For microarray analysis, RNA quality was assessed using Agilent Bioanalyzer. Reverse transcription to cDNA, fragmentation, labeling and hybridization with Human Gene 1.0 ST arrays were performed according to Affymetrix protocols. Functional grouping was carried out using the Ingenuity Pathway Analysis (IPA). Some of the most significantly (P<0.01) regulated genes (≥3-fold) were chosen for validation by qRT-PCR. hCG (100 ng/ml) significantly downregulated IL1R2 expression (P<0.01) in stromal cells; and effect which was maintained in cells subsequently exposed to IL1 (P<0.01) and accompanied by a significant increase in IL1R1 expression (P<0.001), MCP1 secretion (P<0.0001) and endothelial cell growth-promoting activity (P<0.01). Functional grouping (IPA) revealed significant changes in angiogenesis/tissue remodeling, immuno-inflammatory and cell signaling pathways and identified several genes that may play an important role in embryo-maternal signaling. hCG modulates endometrial cell receptivity to IL1, and act in synergy with IL1 to promote angiogenesis and tissue remodeling and modulate immune function at the embryo-maternal interface. This reveals a new mechanism by which hCG sustains human pregnancy and promotes embryonic growth.

Interleukin-1 signaling mediates acute doxorubicin-induced cardiotoxicity

Doxorubicin (DOX) is a potent anticancer drug, which is widely used in the treatments of a variety of solid and hematopoietic tumours, but its use is limited by its cardiotoxicity and dose-dependent congestive heart failure. After we found the high expression of interleukin-1 receptor I (IL-1RI) gene in mice cardiac tissues with DOX-induced cardiotoxicity, we assumed interleukin-1 (IL-1) signaling might mediate acute DOX-induced cardiotoxicity. In this report, Balb/c mice were intraperitoneally injected with different dosage of DOX followed by different days of study. We found both IL-1β and interleukin-1 receptor antagonist (IL-1Ra) concentrations in serum were highly induced after DOX treatment, associated with increased IL-1RI expression in cardiac tissues. Furthermore, IL-1 signaling was found to express higher with the increased dosage of DOX treatment. Histology score of cardiac tissues showed obvious cardiac damage after DOX treatment, while assessment with the Spearman rank correlation coefficient showed that histology score was closely correlated with IL-1β and IL-1Ra concentrations in serum and IL-1RI expression in cardiac tissue. Our results reveal a potential role of IL-1 signaling in acute DOX-induced cardiotoxic injury and lead to an assumption that this signal system might be a potential candidate agent that inhibits cardiomyocyte-toxicity in DOX-exposed patients.

Type II interleukin-1 receptor expression is reduced in monocytes/macrophages and atherosclerotic lesions

Type II interleukin-1 receptor (IL-1R2) is a non-signaling decoy receptor that negatively regulates the activity of interleukin-1 (IL-1), a pro-inflammatory cytokine involved in atherogenesis. In this article we assessed the relevance of IL-1R2 in atherosclerosis by studying its expression in monocytes from hyperlipidemic patients, in THP-1 macrophages exposed to lipoproteins and in human atherosclerotic lesions. Our results showed that the mRNA and protein expression of IL-1R2 was reduced in monocytes from patients with familial combined hyperlipidemia (− 30%, p < 0.05). THP-1 macrophages incubated with increasing concentrations of acetylated low density (ac-LDL) and very low density (VLDL) lipoproteins also exhibit a decrease in IL-1R2 mRNA and protein levels. Pre-incubation with agents that block intracellular accumulation of lipids prevents the decrease in IL-1R2 mRNA caused by lipoproteins. Lipoproteins also prevented the increase in IL-1R1 and IL-1R2 caused by a 4-h stimulation with LPS and reduced protein expression of total and phosphorylated IL-1 receptor-associated kinase-1. Finally, IL-1R2 expression in human atherosclerotic vessels was markedly lower than in non-atherosclerotic arteries (− 80%, p < 0.0005). Overall, our results suggest that under atherogenic conditions, there is a decrease in IL-1R2 expression in monocytes/macrophages and in the vascular wall that may facilitate IL-1 signaling.

Endometrioid ovarian cancer and endometriotic cells exhibit the same alteration in the expression of interleukin-1 receptor II: To a link between endometriosis and endometrioid ovarian cancer

Endometrioid carcinoma of the ovary is the third most common type of epithelial ovarian cancer. Endometrioid tumors as well as endometriotic implants are characterized by the presence of epithelial cells, stromal cells, or a combination of booth, that resemble the endometrial cells, suggesting a possible endometrial origin of these tumors. Th1 cytokines including interleukin (IL)-1 have been reported to be involved in both endometriosis and ovarian carcinogenesis. We assessed the expression of receptors of IL-1 (IL-1RI and IL-1RII, the signal transducer and the specific inhibitor of IL-1, respectively) in cells of the most common subtypes of ovarian cancer compared to endometrial cells. IL1-Rs expression was analyzed at the levels of the protein and mRNA using immunofluorescent and real-time polymerase chain reaction methods, respectively. We showed that endometrioid cells exhibit a specific decrease of IL-1RII expression, whereas IL-1RI was constantly expressed in all studied cell subtypes. As already reported in endometriotic cells, endometrioid ovarian cancer cells exhibit the same alteration in the expression of IL-1RII, a key protector against tumorigenic effects of IL-1. Our findings highlight a common signature between endometrioid ovarian cancer and implants of endometriosis, which needs to be fully explored.

Proinflammatory Orientation of the Interleukin 1 System and Downstream Induction of Matrix Metalloproteinase 9 in the Pathophysiology of Human Perinatal White Matter Damage

A preclinical model showed a direct role of the interleukin 1 (IL-1) system in the pathogenesis of perinatal brain damage, but evidence linking these findings to human white matter damage (WMD) requires confirmation in human cases. We analyzed the IL-1β system using immunohistochemistry to characterize the expression of IL-1 receptors (IL-1R1 and IL-1R2), IL-1R antagonist (IL-1Ra), and induction of downstream effectors in 9 human brains with WMD. Interleukin 1β overexpression was associated with IL-1R1 and IL-1R2 immunoreactivity in areas with WMD; immunolabeling for both was detected on astrocytes and microglia/macrophages. There was no immunoreactivity for these receptors in nondamaged white matter in the same brains. Interleukin-1Ra expression was significantly less upregulated than that of IL-1β. This IL-1β/IL-1Ra imbalance was particularly pronounced in the brains of very preterm versus near-term infants. We additionally found overexpression of matrix metalloproteinase 9 (MMP-9) in WMD areas. The MMP-9 colocalized with IL-1β in microglia/macrophages in affected cerebral areas. These data indicate that there is activation and proinflammatory orientation of the IL-1 system with downstream induction of MMP-9 in perinatal WMD. Because both of these mediators are known to be involved in neural cell injury, we infer that IL-1 pathway activation has a deleterious role in the pathophysiology of WMD in human neonates.

Expression of interleukin-1 receptor-associated kinase-1 in non-small cell lung carcinoma and preneoplastic lesions.

To identify the pattern of interleukin-1 receptor-associated kinase (IRAK-1) protein expression in non-small cell lung carcinoma (NSCLC) and corresponding preneoplastic lesions. Archived tissue from NSCLC (adenocarcinoma and squamous cell carcinoma; n = 306) and adjacent bronchial epithelial specimens (n = 315) were analyzed for the immunohistochemical expression of IRAK-1, and the findings were correlated with patients' clinicopathologic features. Furthermore, we investigated the correlation between IRAK-1 expression and expression of NF-kappaB and IL-1alpha in tumor specimens. NSCLC tumors showed significantly higher cytoplasmic and lower nuclear IRAK-1 expression than normal epithelium. Squamous dysplasias had significantly higher cytoplasmic IRAK-1 expression than normal epithelium. In tumors, a significant positive correlation was detected between IRAK-1 expression (nuclear and cytoplasmic; P = 0.011) and IL-1alpha cytoplasmic expression (P < 0.0001). The correlation between the expression of the markers and patients' clinicopathologic features varied according to tumor histologic type and sex. High IRAK-1 cytoplasmic expression correlated with worse recurrence-free survival in women with NSCLC [hazard ratio (HR), 2.204; P = 0.033], but not in men. In adenocarcinoma, combined low level of expression of nuclear IRAK-1 and NF-kappaB correlated significantly with worse overall (HR, 2.485; P = 0.007) and recurrence-free (HR, 3.058; P = 0.006) survivals in stage I/II patients. IRAK-1 is frequently expressed in NSCLC tissue specimens, and this expression is an early phenomenon in the sequential development of lung cancer. IRAK-1 is a novel inflammation-related marker and a potential target for lung cancer chemopreventive strategies.

Central nervous action of interleukin‐1 mediates activation of limbic structures and behavioural depression in response to peripheral administration of bacterial lipopolysaccharide

Although receptors for the pro-inflammatory cytokine interleukin-1 have long been known to be expressed in the brain, their role in fever and behavioural depression observed during the acute phase response (APR) to tissue infection remains unclear. This may in part be due to the fact that interleukin-1 in the brain is bioactive only several hours after peripheral administration of bacterial lipopolysaccharide (LPS). To study the role of cerebral interleukin-1 action in temperature and behavioural changes, and activation of brain structures during the APR, interleukin-1 receptor antagonist (IL-1ra; 100 microg) was infused into the lateral brain ventricle 4 h after intraperitoneal (i.p.) LPS injection (250 microg/kg) in rats. I.p. LPS administration induced interleukin-1beta (IL-1beta) production in systemic circulation as well as in brain circumventricular organs and the choroid plexus. Intracerebroventricular (i.c.v.) infusion of IL-1ra 4 h after i.p. LPS injection attenuated the reduction in social interaction, a cardinal sign of behavioural depression during sickness, and c-Fos expression in the amygdala and bed nucleus of the stria terminalis. However, LPS-induced fever, rises in plasma corticosterone, body weight loss and c-Fos expression in the hypothalamus and caudal brainstem were not altered by i.c.v. infusion of IL-1ra. These findings, together with our previous observations showing that i.c.v. infused IL-1ra diffuses throughout perivascular spaces, where macrophages express interleukin-1 receptors, can be interpreted to suggest that circulating or locally produced brain IL-1beta acts on these cells to bring about behavioural depression and activation of limbic structures during the APR after peripheral LPS administration.

Neuroinflammation in Parkinson’s patients and MPTP-treated mice is not restricted to the nigrostriatal system: Microgliosis and differential expression of interleukin-1 receptors in the olfactory bulb

Neuroinflammation may play a role in the pathogenesis of Parkinson’s disease (PD). The present study questioned whether this neuroinflammatory response differs between the olfactory bulb, as an early affected region and the nigrostriatal system. Indeed, increased microgliosis was shown in post-mortem olfactory bulb of PD patients. Also in olfactory bulb of MPTP-treated mice, microgliosis and increased expression of IL-1α, IL-1β and IL-1ra mRNA was observed early after treatment. These observations implicate that neuroinflammation is not restricted to the nigrostriatal system. MPTP-induced microgliosis in striatum and olfactory bulb was reduced in IL-1α/β knockout mice, indicating that IL-1 affects microglia activation. Importantly, MPTP induced differential regulation of IL-1 receptors. mRNA levels of IL-1RI and, to a lesser extent, IL-1RII were increased in striatum. Interestingly, in the olfactory bulb only IL-1RII mRNA was enhanced. We suggest that differential regulation of IL-1 signaling can serve as an important mechanism to modulate neuroinflammatory activity after MPTP treatment and possibly during PD.

Expression analysis of the TAB2 protein in adult mouse tissues

.Background:The Interleukin-1 (IL-1) signaling component TAK1 binding protein 2 (TAB2) plays a role in activating the NFκB and JNK signaling pathways. Additionally, TAB2 functions in the nucleus as a repressor of NFκB-mediated gene regulation.Objective:To obtain insight into the function of TAB2 in the adult mouse, we analyzed the in vivo TAB2 expression pattern.Materials and methods:Cell lines and adult mouse tissues were analyzed for TAB2 protein expression and localization.Results:Immunohistochemical staining for TAB2 protein revealed expression in the vascular endothelium of most tissues, hematopoietic cells and brain cells. While TAB2 is localized in both the nucleus and the cytoplasm in cell lines, cytoplasmic localization predominates in hematopoietic tissues in vivo.Conclusions:The TAB2 expression pattern shows striking similarities with previously reported IL-1 receptor expression and NFκB activation patterns, suggesting that TAB2 in vivo is playing a role in these signaling pathways.

Immunolocalization of interleukin‐1 receptors in the sarcolemma and nuclei of skeletal muscle in patients with idiopathic inflammatory myopathies

Interleukin-1 (IL-1) acts via its receptors to induce gene expression that mediates protein synthesis involved in inflammation. Increased expression of IL-1alpha and IL-1beta in muscle tissue from patients with polymyositis and dermatomyositis has been demonstrated. It is not known whether the reciprocal IL-1 receptors are expressed in human muscle tissue. The purpose of this study was to investigate the expression of IL-1 receptors and their ligands in muscle tissue from patients with myositis and from healthy controls. Muscle biopsy tissues from 10 patients with polymyositis or dermatomyositis and 7 healthy control subjects were investigated by immunohistochemistry using antibodies against IL-1 receptor type I (IL-1RI), IL-1RII, IL-1alpha, IL-1beta, and IL-1 receptor antagonist (IL-1Ra). Quantification was performed by computerized image analysis, and localization of expression was determined by double staining using immunofluorescence and confocal microscopy. In tissue samples from the patients, IL-1RI and IL-1RII were expressed in muscle fibers, inflammatory cells, and endothelial cells. Expression in muscle fibers was localized to the sarcolemma and nuclei. IL-1alpha was expressed in endothelial cells and inflammatory cells, whereas IL-1beta and IL-1Ra were expressed only in inflammatory cells. Expression of the two IL-1 receptors and their ligands was significantly higher in patients than in controls. IL-1 receptor expression on muscle fibers was most pronounced in the vicinity of cells expressing IL-1alpha and IL-1beta. The increased expression of IL-1 receptor and the colocalization with reciprocal ligands in patients with myositis but not in healthy controls support the hypothesis of a crucial role of IL-1 in the pathogenesis of polymyositis and dermatomyositis.

Gene regulation by IL‐1β independent of IL‐1R1 in the mouse brain

Interleukin-1 (IL-1) is a key pro-inflammatory cytokine that has diverse actions in the brain as a regulator of host defense responses and a mediator of inflammation. Two major agonists, IL-1alpha and IL-1beta, bind to a single known functional type-1 IL-1 receptor (IL-1RI) that associates with the accessory protein (IL-1RAcP), resulting in signal transduction. However, recent evidence suggests that some actions of IL-1 in the brain may be independent of IL-1R1 and the classical IL-1 signaling pathways, pointing to an as-yet unidentified functional receptor for IL-1. In this study, we have used cDNA microarray-based gene expression profiling to identify the possible genes induced by IL-1beta independently of IL-1R1. IL-1beta induced potential changes (greater than 2-fold vs. vehicle-treated) in the expression of up to 1285 candidate genes in wild-type primary mixed glia, and 404 candidate genes in IL-1R1-/- cells of the same type. Real-time quantitative polymerase chain reaction (PCR) on selected genes revealed that pentraxin-3, was upregulated by IL-1beta in wild-type, but not in IL-1R1-/- mixed glia. Amongst the other genes for which expression was modified by IL-1beta in IL-1R1-/- cells, we selected alpha-syntrophin and demonstrated by real-time quantitative PCR that expression of this gene is significantly downregulated by IL-1beta in primary mixed glia prepared from wild-type, IL-1R1-/-, IL-1RAcP-/- or MyD88-/- mice. In contrast, IL-1alpha fails to downregulate alpha-syntrophin expression in wild-type or IL-1R1-/- mixed glia. These results show that IL-1beta exclusively downregulates alpha-syntrophin expression independently of IL-1R1, and suggest the expression of additional functional IL-1 receptors in the CNS.

Alteration on the Expression of IL-1, PDGF, TGF-β, EGF, and FGF Receptors and c-Fos and c-Myc Proteins in Bone Marrow Mesenchymal Stroma Cells from Advanced Untreated Lung and Breast Cancer Patients

Previously, we reported a deficient cloning capacity of the bone marrow (BM) mesenchymal stem cells to give colony-forming unit fibroblast (CFU-F) and an inefficient confluence capacity of BM stromal cells in advanced untreated lung cancer patients (LCP) and breast cancer patients (BCP). Moreover, a decreased level of bFGF at day 7 in the conditioned media from BM CFU-F cultures was found in both cancer groups when compared to the normal range. The current study was specially undertaken, to evaluate the percentage of subconfluent fibroblasts expressing receptors (R) of interleukin-1 (IL-1), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), transforming growth factor (TGF-beta), epidermal growth factor (EGF), and the proteins c-Fos and c-Myc in BM primary cultures from untreated LCP and BCP. An immunocytochemical study on subconfluent BM fibroblast cultures from 13 healthy patients, 16 LCP, and 8 BCP was performed, using as primary antibodies, anti-type I of IL-1 R (IL-1R-1), anti-alpha, beta chains of PDGF R (PDGFR-alpha, PDGFR-beta), anti-type I of FGF R (FGFR-I), anti-type I, II, and III of TGF-beta R (TGF-betaR-I, TGF- betaR-II, and TGF-betaR-III), anti-EGF R, anti-c-Fos, and anti-c-Myc. A diminished percentage of subconfluent fibroblasts expressing PDGFR-alpha, TGFbetaR-I, II, III, EGFR, and FGFR-I was found in LCP and BCP compared to healthy patients. A diminished percentage of subconfluent fibroblasts expressing c-Fos and c-Myc was found in patients when compared to healthy patients. The alterations we describe could help to explain the deficiency regarding the proliferative and confluence capacity of BM stroma cells in cancer patients.

Cycloprodigiosin up-regulates inducible nitric oxide synthase gene expression in hepatocytes stimulated by interleukin-1β

The proinflammatory cytokine interleukin-1β stimulates inducible nitric oxide synthase (iNOS) gene expression in hepatocytes via activation of a transcription factor, nuclear factor-κB (NF-κB). Nitric oxide has diverse cytoprotective and toxic effects. Cycloprodigiosin is an anticancer drug that induces apoptosis through NF-κB-dependent mechanisms. This study investigated whether cycloprodigiosin influenced NF-κB activation and induction of iNOS by interleukin-1β. Cycloprodigiosin alone had no effect on NO production by primary cultured rat hepatocytes. Simultaneous addition of cycloprodigiosin and interleukin-1β markedly stimulated the induction of iNOS mRNA and protein compared with addition of interleukin-1β alone, resulting in overproduction of NO. Cycloprodigiosin had no effect on degradation of the inhibitory subunit of NF-κB (IκBα), but lessened the recovery of IκBα levels. The electrophoretic mobility shift assay revealed that cycloprodigiosin caused an increase of NF-κB activation. Consistent with this observation, cycloprodigiosin promoted the translocation of p65 (a subunit of NF-κB) to the nucleus. Furthermore, this drug enhanced expression of the type 1 interleukin-1 receptor, and this action showed similar concentration-dependence to its induction of iNOS. These results indicate that cycloprodigiosin up-regulates the induction of iNOS by increasing NF-κB activation, at least partly through enhancement of type 1 interleukin-1 receptor expression. By regulating the expression of NF-κB-dependent genes, such as iNOS, cycloprodigiosin administration may increase NO production during hepatic injury.

Increased toll-like receptor 4 in the myocardium of patients requiring left ventricular assist devices

Background Cytokine activation in the myocardium of deteriorating patients with heart failure who undergo left ventricular assist-device (LVAD) implantation has been documented, but the underlying mechanisms remain poorly understood. We hypothesized the innate immune system is activated with expression of Toll-like receptor 4 (TLR4), leading to cytokine activation in these patients. Methods We used quantitative real-time reverse-transcriptase polymerase chain reaction to measure TLR4, interleukin-1 (IL-1) receptor, IL-1β, IL-6, and tumor necrosis factor α (TNF-α) mRNA expression in myocardial samples from 36 patients. We compared 18 patients who underwent LVAD implantation with 18 patients with less severe heart failure who underwent elective heart transplantation. Results Toll-like receptor 4 expression was 1.69-fold greater ( p < 0.05) and IL-1 receptor expression was 3.64–fold greater ( p < 0.0001) in the deteriorating patients who required LVADs. Myocardial TNF-α (1.71-fold, p < 0.05), IL-6 (2.57-fold, p < 0.005), and IL-1β (9.78-fold, p < 0.001) also were increased in the LVAD candidates. Toll-like receptor 4 expression correlated strongly with IL-1 receptor expression ( r= 0.75, p < 0.0001) and with IL-1 β expression in individual patients ( r = 0.7, p < 0.0001). Interleukin-1 receptor expression also correlated with IL-1β expression ( r = 0.78, p < 0.0001) within patients. We found no correlation between TLR4 and either TNF-α or IL-6 expression. Conclusions Patients who required LVAD support showed evidence of innate immune system activation, indicated by an increase in the key effector molecule TLR4 associated with a specific pattern of cytokine expression in the myocardium.

Interleukin-1 Regulates Proliferation and Differentiation of Oligodendrocyte Progenitor Cells

Interleukin-1 (IL-1) is a pleiotropic cytokine expressed during normal CNS development and in inflammatory demyelinating diseases, but remarkably little is known about its effect on oligodendroglial cells. In this study we explored the role of IL-1β in oligodendrocyte progenitors and differentiated oligodendrocytes. The effects of IL-1β were compared to those of IL-1 receptor antagonist, the specific inhibitor of IL-1 activity, since progenitors and differentiated oligodendrocytes produce IL-1β and express IL-1 receptors. Unlike other proinflammatory cytokines (TNFα and IFNγ), IL-1β was not toxic for oligodendrocyte lineage cells. However, this cytokine inhibited proliferation of oligodendrocyte progenitors in the presence of growth factors (PDGF plus bFGF). This was evidenced by a significant decrease in both cells incorporating bromodeoxyuridine (45%) and total cell numbers (57%) after 6 days of treatment. Interestingly, IL-1β blocked proliferation at the late progenitor/prooligodendrocyte (O4+) stage but did not affect proliferation of early progenitors (A2B5+). Inhibition of proliferation paralleled with promotion of differentiation, as revealed by the increased percentage of R-mab+ cells (6.7-fold). Moreover, when oligodendrocyte progenitors were allowed to differentiate in the absence of growth factors, treatment with IL-1β promoted maturation to the MBP+ stage (4.2-fold) and survival of differentiating oligodendrocytes (2.1-fold). Regarding intracellular signaling, IL-1β activated the p38 mitogen-activated protein kinase (MAPK) but not the p42/p44 MAPK and, when combined with growth factors, intensified p38 activation but inhibited the growth-factor-induced p42/p44 activation. IL-1β also induced a time-dependent inhibition of PFGF-Rα gene expression. These results support a role for IL-1β in promoting mitotic arrest and differentiation of oligodendrocyte progenitors as well as maturation and survival of differentiating oligodendrocytes.

Involvement of the Arcuate Nucleus of the Hypothalamus in Interleukin-1-Induced Anorexia

Cytokine-mediated anorexia is a component of "sickness behavior" and presents a significant obstacle in the treatment of chronic illnesses. We hypothesized an involvement of the hypothalamic arcuate nucleus (ARH) in mediating the anorexic effects of a systemic interleukin-1 (IL-1) challenge based on its content of peptidergic neurons involved in feeding, its expression of IL-1 receptors and its sensitivity to systemic IL-1. IL-1 (6 microg/kg, i.v.) was found to induce Fos expression in both pro-opiomelanocortin- and neuropeptide Y-expressing neurons in and around the ARH. Contrary to expectations, rats that had sustained lesions of the arcuate nucleus, produced by neonatal monosodium glutamate treatment, displayed a more pronounced suppression (by 25%) of food intake than nonlesioned controls when treated with IL-1 after a 20 hr fast. To confirm and further characterize this unexpected result, a second ablation method was used in a similar paradigm. Animals bearing knife cuts designed to sever major ARH projections displayed an even more accentuated loss of appetite (by 60%, relative to controls) in response to systemic IL-1. This effect exhibited at least some degree of specificity, because the knife cuts did not alter either IL-1 effects on another centrally mediated acute phase response (fever) or the anorexia produced by an alternate agent, fenfluramine. These results fail to support the hypothesized ARH mediation of IL-1-induced anorexia and may suggest rather that the net output of this cell group may serve normally to restrain cytokine-induced reductions in food intake.

Initiation of humoral immunity. II. The effects of T-independent and T-dependent antigens on the distribution of lymphocyte populations

The effect of injecting T-independent (lipopolysaccharide, LPS) and T-dependent (bovine serum albumin, BSA) antigens on the redistribution of lymphocyte populations in immature male chickens was investigated. In the blood, percentages of total T-cells (CD3+), T-helper cells (CD4+), and T-cytotoxic/suppressor cells (CD8+) significantly decreased post-LPS injection (PLI) but not post-BSA injection (PBI), while percentages of monocytes/thrombocytes (K1+) significantly increased PLI. Interleukin-1 receptor expression on blood lymphocytes increased significantly PLI and PBI. In the spleen, the percentages of total T-cells (CD3+) increased significantly PLI and PBI, macrophage (K1+) percentages increased significantly PLI, while B-cell percentages decreased significantly PLI. These results indicate that following antigen injection, there is a redistribution of peripheral blood lymphocytes (specifically T-lymphocytes) to secondary lymphoid organs and the kinetics and magnitude of the changes can differ according to the type of antigen used.

Relationship of the interleukin-1 system with neuroendocrine and exocrine markers in human colon cancer cell lines.

Interleukin 1 (IL-1) is known to regulate the proliferation and differentiation of normal and malignant immune cells as well as other cell types. Expression of IL-1 (alpha and beta), IL-1 receptors (RI and RII) and IL-1 receptor antagonist (IL-1RA) was determined by RT-PCR in seven human colon carcinoma cell lines (COLO 320DM, LoVo, SW403, SW1116, SW1417, LS123 and LS174t). Influence of IL-1 on the secretion of the neuroendocrine (NE) differentiation marker chromogranin A (CGA) and the exocrine marker carcinoembryonic antigen (CEA) was examined by Western blotting. Our data indicate that CGA and IL-1RI are expressed by all seven, IL-1 beta by five, IL-1RII and IL-1RA by six lines. IL-1 alpha transcripts were found only in three lines (LoVo, SW1116 and LS174t) and correlated with high CEA levels and aggressive growth behavior. "Pure" NE cell lines (COLO 320DM and LS123) secreted the highest levels of CGA, but the lowest levels of CEA and were IL-1 (alpha and beta) negative. Exogenously added IL-1 caused a decrease in CGA, but an increase in CEA secretion. Our results suggest an inverse relationship between IL-1 and NE differentiation, as well as a direct relationship between IL-1 and CEA expression in colon carcinoma.

Age-related regional difference of interleukin-1 expression in rat brain after lipopolysaccharide treatment.

Aging is associated with altered immune responses including dysregulation of cytokine production. Of cytokines, interleukin-1 (IL-1) family has been primarily involved with central nervous system. To evaluate the age-related different response of IL-1 family following peripheral administration of lipopolysaccharide (LPS), immunohistochemical study of IL-1beta and IL-1 receptor expression was performed on Sprague-Dawley rat brain. Experimental animals were divided into four groups; saline-treated young (3-5 months) and old (over 24 months), and LPS-treated young and old groups. After intraperitoneal (i.p.) injection of LPS, three to five rats within each group were killed at 1, 2, 4, 8 and 16 hr. After fixation in 4% neutral buffered formalin, the brain slices were paraffin-embedded. Immunohistochemical staining using labelled streptavidin biotin was performed. The results showed that IL-1beta immunoreactivity was seen in the endothelial cell of pons in both LPS-treated young and old rats, with slightly longer persistency in old group. IL-1RI immunoreactivity appeared initially in the neurons of cerebral cortex in LPS-treated old group, compared with predominantly the cerebellum in LPS-treated young group. In conclusion, our study shows that there is age-related, different neuronal localization of IL-1RI expression at different points of time after LPS treatment.

Expression of interleukin-1 receptors in the later period of foetal thymic organ culture and during suspension culture of thymocytes from aged mice.

Interleukin-1 has been reported to be involved in thymocyte development by exerting a variety of effects on immature CD4-CD8- double-negative (DN) thymocytes. In contrast to the well-documented involvement of IL-1 in thymocyte development, expression of IL-1 receptors (IL-1R) on thymocytes has not been well demonstrated. In the present study, expression of IL-1R on the developing thymocytes was investigated. Although normal thymocytes barely express IL-1R, expression of IL-1R (type I) substantially increased at days 12-15 of foetal thymic organ culture (FTOC), with an increase of the DN subset. The CD4/CD8 profile of the IL-1R (type I)+ cells showed that these cells were mostly restricted to the DN and CD4+CD8+ subsets. Interestingly, in vitro culture of the thymocytes from an aged mouse, but not those from young adult or newborn mice, revealed similar results to those of FTOC. In addition, half of the IL-1R+ cells that increased in the later period of FTOC were gammadelta thymocytes. These results demonstrate IL-1R expression on thymocytes during ex vivo culture and suggest that IL-1R is expressed in a certain environment during normal thymocyte differentiation.