Peripheral blood neutrophil production of interleukin-1 receptor antagonist and interleukin-1β

Journal of Clinical Immunology - The objective of this study was to characterize interleukin-1 receptor antagonist (IL-1ra) and interleukin-1β (IL-1β) production by human peripheral blood...     

Decreased expression of P-glycoprotein in interleukin-1β and interleukin-6 treated rat hepatocytes

OBJECTIVE AND DESIGN: As acute inflammation is known to cause a reduction in hepatic P-Glycoprotein (PGP) expression and activity in rats, we tested the hypothesis that the pro-inflammatory cytokines interleukin (IL-)1beta and IL-6 also mediate reductions in PGP. METHODS: Hepatocytes were incubated with 0-50 ng/ml of cytokine for 24-72 h. PGP/mdr expression was examined by immunodetection and quantitative RT-PCR analysis and PGP efflux activity was assayed. RESULTS: PGP protein was significantly reduced in cells treated for 3 days with IL-1beta and 24 h with IL-6 (p < 0.05), maximal effects occurring at 5 ng/ml for each cytokine. PGP activity was reduced in both IL-1beta and IL-6 treated cells (p < 0.05). mdr1 mRNA was decreased in cells treated with IL-6, but not IL-1beta. spgp and mdr2 were not affected. CONCLUSIONS: Our data indicate that IL-6 and IL-1beta have suppressive effects on the expression and activity of PGP in cultured hepatocytes, likely occurring through distinct mechanisms. These cytokines may have a potential role in PGP regulation during inflammatory responses.     

Effect of interferon-γ, interleukin-2 and interleukin-4 on cyclosporin-a-mediated inhibition of anti-CD3-induced T-lymphocyte proliferation

It is generally believed that cyclosporin A (CsA) inhibits T-cell activation largely by blocking interleukin (IL)-2 production, although CsA also inhibits the secretion of other growth-promoting lymphokines. To investigate the importance of downregulated synthesis of IL-4 and interferon (IFN)-γ, in addition to IL-2, in CsA-mediated inhibition of T-lymphocyte proliferation, exogenous IL-2, IL-4, and IFN-γ were added to murine T-cells stimulated with anti-CD3 monoclonal antibody in the presence of an inhibitory concentration of CsA. Either IL-2 or IL-4 alone were able to partially counteract the inhibitory effect of CsA on anti-CD3-induced T-lymphocyte proliferation, whereas IFN-γ had no discernable effect. IL-2 and IL-4, in combination, were able to largely reverse the immunosuppressive activity of CsA. These results indicate that (1) CsA fails to block T-cell signal transduction pathways coupled to IL-2 and IL-4 receptors, and (2) IL-2 and IL-4 have an additive effect in promoting the proliferation of a heterogenous T-cell population stimulated with anti-CD3 monoclonal antibody.     

Response of human engineered cartilage based on articular or nasal chondrocytes to interleukin-1β and low oxygen

Previous studies showed that human nasal chondrocytes (HNC) exhibit higher proliferation and chondrogenic capacity as compared to human articular chondrocytes (HAC). To consider HNC as a relevant alternative cell source for the repair of articular cartilage defects it is necessary to test how these cells react when exposed to environmental factors typical of an injured joint. We thus aimed this study at investigating the responses of HNC and HAC to exposure to interleukin (IL)-1β and low oxygen. For this purpose HAC and HNC harvested from the same donors (N=5) were expanded in vitro and then cultured in pellets or collagen-based scaffolds at standard (19%) or low oxygen (5%) conditions. Resulting tissues were analyzed after a short (3 days) exposure to IL-1β, mimicking the initially inflammatory implantation site, or following a recovery time (1 or 2 weeks for pellets and scaffolds, respectively). After IL-1β treatment, constructs generated by both HAC and HNC displayed a transient loss of GAG (up to 21.8% and 36.8%, respectively) and, consistently, an increased production of metalloproteases (MMP)-1 and -13. Collagen type II and the cryptic fragment of aggrecan (DIPEN), both evaluated immunohistochemically, displayed a trend consistent with GAG and MMPs production. HNC-based constructs exhibited a more efficient recovery upon IL-1β withdrawal, resulting in a higher accumulation of GAG (up to 2.6-fold) compared to the corresponding HAC-based tissues. On the other hand, HAC displayed a positive response to low oxygen culture, while HNC were only slightly affected by oxygen percentage. Collectively, under the conditions tested mimicking the postsurgery articular environment, HNC retained a tissue-forming capacity, similar or even better than HAC. These results represent a step forward in validating HNC as a cell source for cartilage tissue engineering strategies.     

Gene polymorphisms of interleukin-4, interleukin-10 and transforming growth factor-beta in Graves’ disease

Among genetic factors that may contribute to the development and progression of Graves’ disease (GD) and its complications are polymorphisms in the genes encoding cytokines. The association between GD and the following polymorphisms in anti-inflammatory cytokines was studied in 107 patients with GD and 140 healthy controls: IL-4 (−1098T/G, −590T/C, −33C/T), IL-10 (−1082A/G, −819C/T, −592C/A) and TGF-β (+869T/C, +915G/C). The following alleles and genotypes were significantly (P < 0.01 after correction for multiple testing) more frequent among patients: the IL-4 −1098G allele and GG genotype (OR = 3.12 and 105.00, respectively), IL-4 −33T allele and TT genotype (OR = 2.52 and 118.83, respectively), IL-10 −1082G allele and GG genotype (OR = 2.16 and 6.40, respectively), IL-10 −819T allele, TC and TT genotype (OR = 2.60, 3.68 and 6.76, respectively), IL-10 −592A allele, AC and AA genotype (OR = 2.41, 2.89 and 5.68, respectively), TGF-β +869C allele and CC genotype (OR = 2.24 and 6.21, respectively), and TGF-β +915C allele, CG and CC genotype (OR = 7.81, 11.80 and 20.40, respectively). The only allele and genotype with a lower frequency in patients were IL-4 −590T allele and TC genotype (OR = 0.47 and 0.08, respectively; P < 0.01). In conclusion, this study highlighted the importance of anti-inflammatory cytokine gene polymorphisms in susceptibility to GD.     

Elevated serum levels of interleukin-6, interleukin-1β and human chorionic gonadotropin in pre-eclampsia

Citation Kalinderis M, Papanikolaou A, Kalinderi K, Ioannidou E, Giannoulis C, Karagiannis V, Tarlatzis BC. Elevated serum levels of interleukin‐6, interleukin‐1β and human chorionic gonadotropin in pre‐eclampsia. Am J Reprod Immunol 2011; 66: 468–475 Problem Pre‐eclampsia (PE) is a pregnancy‐specific syndrome of unknown aetiology. It is believed to involve an inflammatory process. The aim of the study was to investigate and compare the concentrations of two proinflammatory cytokines interleukin‐6 (IL‐6) and interleukin‐1β (IL‐1β) and to evaluate the possible interaction between them and human chorionic gonadotropin (hCG) in women with normotensive pregnancy and PE. Method of study A prospective case–control study was carried out in 30 women with PE and 30 normotensive controls. Serum IL‐1β, IL‐6 and hCG levels were determined by enzyme‐linked immunosorbent assay (ELISA) and automated immunofluorescent assay, respectively. Results Serum IL‐6, IL‐1β and hCG levels were significantly increased in women with PE compared to controls (P < 0.001 for each); however, no correlation was found between IL‐6, IL‐1β and hCG. Conclusion Our results highlight the inflammatory origin of PE and reinforce the possible role of hCG in the complex aetiology of its pathogenesis.     

Involvement of NK 1.1-positive γδT cells in interleukin-18 plus interleukin-2-induced interstitial lung disease

Interstitial lung disease (ILD) is induced by various factors in humans. However, the exact mechanism of ILD remains elusive. This study sought to determine the role of natural killer (NK) 1.1(+) γδT cells in ILD. The injection of IL-18 plus IL-2 (IL-18/IL-2) into C57BL6 (B6) mice induced acute ILD that resembled early-stage human ILD. An accumulation of NK1.1(+) γδT cells similar to NK cells was evident in the lungs. The T Cell Receptor (TCR) Vγ and Vδ repertoires of NK1.1(+) γδT cells indicated polyclonal expansion. The expression of IL-2 receptor β (Rβ) and IL-18Rβ in NK1.1(+) γδT cells was higher than in NK1.1(-) γδT cells. IL-18/IL-2 stimulated the proliferation of NK1.1(+) γδT cells, but not NK1.1(-) γδT cells. The IL-18/IL-2-stimulated NK1.1(+) γδT cells produced higher concentrations of IFN-γ than did NK1.1(-) γδT cells. Moreover, NK1.1(+) γδT and NK1.1(-) γδT cells constituted completely different cell populations. The IL-18/IL-2-induced ILD was milder in TCRδ(-/-) and IFN-γ(-/-) mice, compared with B6 mice. Furthermore, cell-transfer experiments demonstrated that NK1.1(+) γδT cells could induce the expansion of NK cells and IFN-γ mRNA in the lung by IL-18/IL-2. Our results suggest that NK1.1(+) γδT cells function as inflammatory mediators in the early phase of IL-18/IL-2-induced ILD.     

Alternation of interleukin-1α production and interleukin-1α binding sites in mouse brain during rabies infection

Summary We have evaluated the effect of rabies virus infection on interleukin-1(IL-1) production and its receptors in mouse brain. Study of virus dissemination in the central nervous system (CNS) showed a massive infection of main brain structures from day 4 post infection (p.i.) up to the agony stage on day 6 p.i. At the same time, IL-1 concentrations increased in cortical and hippocampal homogenates, whereas no change was detected in serum. In non-infected mice, IL-1 binding sites were observed in the dentate gyrus, the cortex, the choroid plexus, the meninges and the anterior pituitary. During rabies virus infection, a striking decrease in IL-1 binding sites was observed on day 4 p.i. with a complete disappearance on day 6 p.i., except in the pituitary gland where they remained at control level. In conclusion, concomitantly with the early rabid pathological signs, brain IL-1 production and IL-1 binding sites are specifically and significantly altered by brain viral proliferation. These results indicate that IL-1 could be involved in the brain response to viral infection as a mediator and could participate in the genesis of the rabies pathogeny.     

Distribution of interleukin-1 receptor complex at the synaptic membrane driven by interleukin-1β and NMDA stimulation

Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that contributes to neuronal injury in various degenerative diseases, and is therefore a potential therapeutic target. It exerts its biological effect by activating the interleukin-1 receptor type I (IL-1RI) and recruiting a signalling core complex consisting of the myeloid differentiation primary response protein 88 (MyD88) and the IL-1R accessory protein (IL-1RAcP). This pathway has been clearly described in the peripheral immune system, but only scattered information is available concerning the molecular composition and distribution of its members in neuronal cells. The findings of this study show that IL-1RI and its accessory proteins MyD88 and IL-1RAcP are differently distributed in the hippocampus and in the subcellular compartments of primary hippocampal neurons. In particular, only IL-1RI is enriched at synaptic sites, where it co-localises with, and binds to the GluN2B subunit of NMDA receptors. Furthermore, treatment with NMDA increases IL-1RI interaction with NMDA receptors, as well as the surface expression and localization of IL-1RI at synaptic membranes. IL-1β also increases IL-1RI levels at synaptic sites, without affecting the total amount of the receptor in the plasma membrane. Our results reveal for the first time the existence of a dynamic and functional interaction between NMDA receptor and IL-1RI systems that could provide a molecular basis for IL-1β as a neuromodulator in physiological and pathological events relying on NMDA receptor activation.     

Identification of the mRNA encoding interleukin-6 and its receptor,interleukin-6 receptor α, in five marsupial species

Expressed coding sequences for interleukin-6 (IL-6) and interleukin-6 receptor α (IL-6R) were examined in five marsupial species. Full length expressed coding sequences for IL-6 and IL-6R were identified and characterized in the gray short-tailed opossum (Monodelphis domestica). For IL-6, ∼225 bp fragments of the mRNA sequence were identified in the red-tailed phascogale (Phascogale calura), kultarr (Antechinomys laniger), and stripe-faced dunnart (Sminthopsis macroura), while ∼563 bp fragments of mRNA encoding IL-6R were identified in the red-tailed phascogale, kultarr, stripe-face dunnart and fat-tailed dunnart (Sminthopsis crassicaudata). Relative expression levels of IL-6 and IL-6R were examined in the heart, muscle, lung, liver, spleen and kidney of adult red-tailed phascogales, and IL-6 gene expression was found to be significantly higher in the lung and spleen than the other tissues examined, while the expression of IL-6R was significantly higher in the liver, lung and spleen. These results now serve as a reference point for examining the role and levels of IL-6 and IL-6R in the health and disease of these marsupial species. The pro-tumorigenic nature of IL-6 is of particular interest, and the identification of these IL-6 and IL-6R coding sequences provides a platform for further work to evaluate the potential role of IL-6 in marsupial cancers.     

Physical activity and plasma interleukin-6 in humans – effect of intensity of exercise

The present study included data from three marathon races to investigate the hypothesis that a relationship exists between running intensity and elevated concentrations of interleukin (IL)-6 in plasma. The study included a total of 53 subjects whose mean age was 30.6 [95% confidence interval (CI) 1.4] years, mean body mass 77.7 (95%CI 2.0) kg, mean maximal oxygen uptake (V˙O_2max) 59.3 (95%CI 1.4) ml · min⁻¹ · kg⁻¹, and who had participated in the Copenhagen Marathons of 1996, 1997 or 1998, achieving a mean running time of 206 (95%CI 7) min. Running intensity was calculated as running speed divided by V˙O_2max. The concentration of IL-6 in plasma peaked immediately after the run. There was a negative correlation between peak IL-6 concentration and running time (r=−0.30, P < 0.05) and a positive correlation between peak IL-6 concentration and running intensity (r=0.32, P < 0.05). The IL-1 receptor antagonist (IL-1ra) plasma concentration peaked 1.5 h after the run and there was a positive correlation between the peak plasma concentrations of IL-6 and IL-1ra (r=0.39, P < 0.01). Creatine kinase (CK) plasma concentration peaked on the 1st day after the run, but no association was found between peak concentrations of IL-6 and CK. In conclusion, the results confirmed the hypothesized association between plasma IL-6 concentration and running intensity, but did not confirm the previous finding of a connection between IL-6 plasma concentration and muscle damage. Accepted: 6 August 2000     

Universalization of health or of social security?

This article presents an analysis of the architecture of Mexico's health system based on the main economic problem, failing to achieve a GDP growth rate to increase real wages and give workers in formal employment coverage social security. This analysis describes the relationship between social security of the population and employment status of it (either formal or informal employment) and the impact that this situation poses to our health system. Also, it ends with a reform proposal that will give all workers the same social rights, ie to grant universal social security.     

The psychomodulatory action of subpyrogenic doses of interleukin-1β in conditions of chronic administration to rats

The effects of interleukin-1β at low, subpyrogenic doses on behavior were studied in rats. Signs of increased anxiety were evident by day 5 of treatment courses. These results provide evidence supporting the role of proinflammatory cytokines in the pathogenesis of emotional disorders. __________ Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 92, No. 3, pp. 299–307, March, 2006.     

Dose- and time-dependent effects of histamine on hypothalamic levels of interleukin-1β in rats

Some recent studies give support to the potential interaction between histamine (HA) and interleukin-1 (IL-1) in the central nervous system (CNS). At the peripheral level, HA acts as an immune modulator, but little is known on the neuroimmune role of this biogenic amine in the CNS. In the present study we have investigated the effects of HA, mepyramine, famotidine, thioperamide, and L-histidine on hypothalamic IL-1. HA induced a time- and dose-dependent decrease in the concentration of IL-1. The maximum effect was obtained 30 minutes after injection. The HA-induced IL-1 response in the hypothalamus was not inhibited by either mepyramine, famotidine or thioperamide. In addition, L-histidine exerted the same effect as HA. The interaction between HA and IL-1 in the CNS might be linked to neuroendocrine regulation as well as to neurotrophic activity and neuroimmune function.     

Pathogenetic role and clinical significance of interleukin-1β in cancer

In recent years, pro-oncogenic mechanisms of the tumour microenvironment (ТМЕ) have been actively discussed. One of the main cytokines of the TМЕ is interleukin-1 beta (IL-1β), which exhibits proinflammatory properties. Some studies have shown an association between an increase in IL-1β levels and tumour progression. The purpose of this review is to analyse the pathogenic mechanisms induced by IL-1β in the TМЕ, as well as the diagnostic significance of the presence of IL-1β in patients with cancer and the efficacy of treatment with IL-1β inhibitors. According to the literature, IL-1β can induce an increase in tumour angiogenesis due to its effects on the differentiation of epithelial cells, pro-angiogenic molecule secretion and expression of adhesion molecules, thus increasing tumour growth and metastasis. IL-1β is also involved in the suppression of anti-tumour immune responses. The expression and secretion of IL-1β has been noted in various types of tumours. In some clinical studies, an elevated level of IL-1β was found to be associated with low efficacy of anti-cancer therapy and a poor prognosis. In most experimental and clinical studies, the use of IL-1β inhibitors contributed to a decrease in tumour mass and an increase in the response to anti-tumour drugs.     

Effect of β-carotene on the development of adjuvant-induced arthritis and production of interleukin-1 in rats

Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 116, N ^o 12, pp. 611–613, December 1993     

Is there an interaction between interleukin-10 and interleukin-22?

Interleukin(IL)-10 and IL-22 are structurally related cytokines. Their heterodimeric receptors consist of the cytokine-specific chains IL-10R1 and IL-22R1, respectively, and the common chain IL-10R2. This study focused on the question of whether IL-10 modulates IL-22 effects and vice versa. This question is important because IL-10 and IL-22 exert anti- and proinflammatory effects, respectively, and, as we show here, are simultaneously present in both systemic and local inflammation. The revealed lacking concomitance of IL-10R1 and IL-22R1 on identical cells excluded any possible interaction between IL-10 and IL-22 apart from the competition for IL-10R2. To study this competition, monocytes and hepatocytes were chosen. The dependence of the cytokine action on IL-10R2 was verified. Interestingly, no influence of IL-22 on IL-10 effects was observed. The same was true when IL-22 was used in complex with IL-22-binding protein. Similarly, no influence of IL-10 was found on IL-22 action. This missing competition seemed to be due to a lack of binding between IL-10R2 and the native cytokines in the absence of their corresponding R1 chain. However, IL-10R2 interacted with defined IL-10- and IL-22-derived peptides supporting the hypothesis that cytokine binding to its corresponding R1 chain creates a binding site on this cytokine for IL-10R2.     

Molecular cloning of chicken interleukin-5 receptor α-chain and analysis of its binding specificity

Interaction between interleukin (IL)-5 and its receptor (IL-5R) is important for the regulation of immunity against worm infections, allergic reactions and B cell response in mammals. In this study, we identified a full-length cDNA encoding chicken IL-5R α-chain (chIL-5Rα). The deduced amino acid sequence showed 41-43% identity to mammalian homologues. It has four well-conserved cysteines and a WSXWS motif in the extracellular region, and a PPXP motif in the cytoplasmic region. Quantitative RT-PCR analysis revealed that chIL-5Rα mRNA expression was markedly high in bone marrow and relatively high in spleen and lung. Recombinant proteins of soluble chIL-5Rα and cytokines (artificially produced chIL-5 (achIL-5) and another IL-5-like molecule KK34) were expressed by 293F cells to examine the cytokine-receptor interactions. Interaction assay using a Biacore biosensor showed that chIL-5Rα has the capability to bind with monomeric achIL-5, but not with KK34. In conclusion, chicken has an IL-5Rα homologue but KK34 does not complement the IL-5/IL-5R system.