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.     

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.     

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.     

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.     

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.     

Is interleukin-6 important in inflammatory bowel disease?

The IL-6 gene maps to an area of chromosome 7 known to be significant for susceptibility to inflammatory bowel disease. The functional effects of interleukin-6 (IL-6) polymorphisms in the 4th intron and in the 3' flanking region of IL-6 gene were studied in 192 inflammatory bowel disease patients and healthy subjects. A polymerase chain reaction with sequence-specific primers (PCR-SSP) was used to determine a G to A polymorphism (* at position 4470 in intron 4 of IL-6 gene). Four alleles in the 3' flanking region were studied using a variable number of tandem repeats PCR (VNTR-PCR) amplification. Production of IL-6 was measured in lipopolysaccharide (LPS) stimulated whole blood samples by an enzyme-linked immunosorbent assay (ELISA). A modest increase in the frequency of the IL-6*G allele was noted in Crohn's disease (CD) patients (50%) and ulcerative colitis (UC) patients (46.1%) as compared to controls (39.8%, P = 0.025). We were unable to find any significant functional effect of the IL-6 polymorphisms tested on IL-6 protein production. We postulate that the IL-6 polymorphisms investigated here may be in linkage disequilibrium with a susceptibility gene and that they may be utilised as genetic markers.     

Neuropeptides stimulate production of interleukin-1β, interleukin-6, and tumor necrosis factor-α in human dental pulp cells

Objective:Orthodontic tooth movement causes inflammatory reactions in the periodontal membrane and dental pulp. It has been reported that substance P (SP) and calcitonin gene-related peptide (CGRP), both sensory neuropeptides, are manifested in the dental pulp of rats during experimental tooth movement, suggesting that they might be involved in the dental pulp inflammation during orthodontic tooth movement. However, the relationships between neuropeptides and pro-inflammatory cytokines have not been fully elucidated.Materials and methods:Human dental pulp (HDP) fibroblasts were prepared from 6 healthy young volunteers (3 males, 3 females; 15–25 years old) during the course of orthodontic treatment. HDP cells were incubated for 24 h in fresh medium containing 2% FCS in the presence of various concentrations of CGRP (10^–12 to 10^–4 M) and SP (10^–12 to 10^–4 M), and the levels of interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)- present in the media were determined using commercially available high-sensitivity enzyme-linked immunosorbent assay kit.Results:We examined the effects of stimulation by these neuropeptides on the production of inflammatory cytokines in HDP fibroblasts, and found that the levels of IL-1, IL-6, and TNF- increased in a time- and concentration-dependent manner. However, the neuropeptides did not act synergistically to increase cytokine secretion in HDP cells or significantly modify LPS-induced cytokine production by HDP cells.Conclusions:Our results suggest that human pulp fibroblasts may be involved in the progress of inflammation in pulp tissue during orthodontic tooth movement, as they produced large amounts of IL-1, IL-6, and TNF- following stimulation with neuropeptides.Received 2 March 2003; returned for revision 14 July 2003; accepted by M.J. Parnham 17 December 2003     

Targeting interleukin-4 in asthma: lost in translation?

The first discovery that interleukin-4 (IL-4) is crucial in the development of allergic airway inflammation originates from the early 1990s. Whereas initial studies in experimental animal models provided the community with the optimistic view that targeting IL-4 would be the ultimate solution for treating asthma, the translation of these findings to the clinic has not been evident and has not yet fulfilled the expectations. Many technical challenges have been encountered in the attempts to modulate IL-4 expression or activity and in transferring knowledge of preclinical studies to clinical trials. Moreover, biological redundancies between IL-4 and IL-13 have compelled a simultaneous blockade of both cytokines. A number of phase I/II studies are now providing us with clinical evidence that targeting IL-4/IL-13 may provide some clinical benefit. However, the initial view that asthma is a purely Th2-mediated disease had to be revised. Currently, different asthma phenotypes have been described, implying that blocking specifically Th2 cytokines, such as IL-4, IL-5, and IL-13, should be targeted to only a specific subset of patients. Taking this into consideration, IL-4 (together with IL-13) deserves attention as subject of further investigations to treat asthma. In this review, we will address the role of IL-4 in asthma, describe IL-4 signaling, and give an overview of preclinical and clinical studies targeting the IL-4 Receptor pathway.     

Intravenous immunoglobulin induces interferon-γ and interleukin-6in vivo

Immunoglobulin is known to be an immunomodulator. It can induce protein mediators from mononuclear cells, particularly monocytesin vitro. Intravenous immunoglobulin (IVIg) has been used as a therapy in several clinical situations. In this study, the influence of IVIg infusion on the plasma levels of two protein mediators, interferon- (IFN-) and interleukin-6 (IL-6), was assessed in patients with secondary generalized epilepsy. Compared to preinfusion levels, plasma interferon- was increased in 18 of 18 patients 20 min after the 6- to 8-hr infusion of IVIg. Plasma interferon- levels reached their peak at various times from 20 min to 3 days post IVIg infusion, dependent upon the individual patient. Plasma IL-6 levels also increased after IVIg infusion. Generally, IL-6 reached its peak level after IFN-. No activated T cells or B cells were observed as determined by the expression of surface CD25, CD23, and HLA-DR 20 min following the infusion when the IFN- and IL-6 levels were assessed. The expression of the high-affinity receptor for IgG, CD64, on monocytes was significantly enhanced after IVIg infusion, while the low-affinity receptor for IgG, CD32, was only slightly increased. Cytoplasmic staining of PBMC indicates that both CD16-positive and CD16-negative cells may contribute to the increase seen in plasma IFN-. These data raise the possibility that the therapeutic effects of intravenous immunoglobulin may be related, at least in part, to the immunomodulatory activity as demonstrated by the changes in plasma levels of IFN- and IL-6.     

Effects of high mobility group box protein-1, interleukin-1β, and interleukin-6 on cartilage matrix metabolism in three-dimensional equine chondrocyte cultures

The effects of high mobility group box protein (HMGB)-1, interleukin (IL)-1β, and IL-6 on equine articular chondrocytes were investigated, with emphasis on detecting differences between anatomical sites exposed to different loading in vivo, using three-dimensional (3D) cell cultures established with chondrocytes from dorsal radial facet (DRF, highly loaded) and palmar condyle (PC, less loaded) of the third carpal bone (C3). Expression of important genes involved in cartilage metabolism, presence of glycosaminoglycans and cartilage oligomeric matrix protein (COMP) in pellets, and concentrations of matrix metalloproteinase (MMP)-13 and aggrecan epitope CS 846 were evaluated. Compared to controls, IL-1β treatment increased gene expression of versican, matrix-degrading enzymes, and tissue inhibitor of metalloproteinase (TIMP)-1, and decreased aggrecan and collagen type I and type II expression. In addition, IL-1β-treated pellets showed decreased safranin O staining and increased COMP immunostaining and MMP-13 concentrations in culture supernatants. Effects of IL-6 and HMGB-1 on gene expression were variable, although upregulation of Sry-related high-mobility group box 9 (Sox9) was often present and statistically increased in HMGB-1-treated pellets. Response to cytokines rarely differed between DRF and PC pellets. Thus, site-associated cartilage deterioration in equine carpal osteoarthritis (OA) is not explained by topographically different responses to inflammatory mediators. Differences in gene expressions of structural matrix proteins in untreated DRF and PC pellets were noted in the youngest horses, which may indicate differences in the chondrocytes potential to produce matrix in vivo. Overall, a strong catabolic response was induced by IL-1β, whereas slight anabolic effects were induced by IL-6 and HMGB-1.     

Effects of high mobility group box protein-1, interleukin-1β, and interleukin-6 on cartilage matrix metabolism in three-dimensional equine chondrocyte cultures

The effects of high mobility group box protein (HMGB)-1, interleukin (IL)-1β, and IL-6 on equine articular chondrocytes were investigated, with emphasis on detecting differences between anatomical sites exposed to different loading in vivo, using three-dimensional (3D) cell cultures established with chondrocytes from dorsal radial facet (DRF, highly loaded) and palmar condyle (PC, less loaded) of the third carpal bone (C3). Expression of important genes involved in cartilage metabolism, presence of glycosaminoglycans and cartilage oligomeric matrix protein (COMP) in pellets, and concentrations of matrix metalloproteinase (MMP)-13 and aggrecan epitope CS 846 were evaluated. Compared to controls, IL-1β treatment increased gene expression of versican, matrix-degrading enzymes, and tissue inhibitor of metalloproteinase (TIMP)-1, and decreased aggrecan and collagen type I and type II expression. In addition, IL-1β-treated pellets showed decreased safranin O staining and increased COMP immunostaining and MMP-13 concentrations in culture supernatants. Effects of IL-6 and HMGB-1 on gene expression were variable, although upregulation of Sry-related high-mobility group box 9 (Sox9) was often present and statistically increased in HMGB-1-treated pellets. Response to cytokines rarely differed between DRF and PC pellets. Thus, site-associated cartilage deterioration in equine carpal osteoarthritis (OA) is not explained by topographically different responses to inflammatory mediators. Differences in gene expressions of structural matrix proteins in untreated DRF and PC pellets were noted in the youngest horses, which may indicate differences in the chondrocytes potential to produce matrix in vivo. Overall, a strong catabolic response was induced by IL-1β, whereas slight anabolic effects were induced by IL-6 and HMGB-1.     

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.     

Prolonged exposure of naïve CD8+ T cells to interleukin-7 or interleukin-15 stimulates proliferation without differentiation or loss of telomere length

Interleukin (IL)‐7 and IL‐15 are cytokines implicated in homeostatic control of the peripheral CD8 T‐cell pool. We compared the effects of IL‐7 and IL‐15 on survival and proliferation of purified human CD8⁺ T‐cell subsets. Low concentrations of either cytokine reduced the spontaneous apoptosis of all subsets, and enhancement of survival corresponded to the extent of Bcl‐2 up‐regulation. Surprisingly, although minimal proliferation of naïve CD8⁺ T cells was observed during the first week of culture with cytokines, a marked expansion of these cells occurred at later time points, particularly in response to IL‐15. This occurred largely without phenotypic change or acquisition of effector function, indicating a dissociation of differentiation from proliferation. Notably, progression of naïve CD8⁺ T cells through several cell divisions resulted in up‐regulation of telomerase and the maintenance of telomere length. These data show that IL‐7 and IL‐15 induce cell proliferation and rescue from apoptosis in a concentration, time and subset‐dependent manner, and have implications for the homeostatic expansion of the naïve CD8⁺ T‐cell pool.     

Pro-inflammatory cytokine interleukin-1β promotes the development of intestinal stem cells

Objective

We investigated the effect of IL-1β on the development of intestinal epithelial stem cells.

Materials and methods

Normal intestinal epithelial cell line IEC-18 cells were cultured in the presence or absence of 200?pM of IL-1β in serum-free medium (SFM) for various time periods. The effects of IL-1β on intestinal stem cell self-renewal and IEC-18 cell proliferation were evaluated by a colony formation assay, MTT assay, and a focus formation assay. The expression of stemness genes including Bmi-1, Lgr-5, c-myc, Nanog, and β-catenin in IEC-18 cells were measured by quantitative PCR and western blot analysis.

Results

IEC-18 cells grew as a monolayer in SFM in the absence of IL-1β. Cellular spheres were formed when IEC-18 cells were grown in SFM in the presence of IL-1β. IL-1β induced the development of large colonies in the soft-agar as well as the formation of foci when IEC-18 cells were cultured in type-I collagen-coated plates. The expression of Bmi-1, Lgr-5, c-myc, Nanog, and β-catenin were significantly increased in IEC-18 cells treated with IL-1β.

Conclusion

Our studies provide direct evidence the IL-1β may play an important role in the self-renewal of intestinal epithelial stem cells and the development of cancer stem cells.