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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Understanding the sources of variation in airway reactivity and airflow is important for unraveling the pathophysiology of asthma, obstructive lung disease, and other pulmonary disorders. Transgenic expression of two closely related cytokines in the mouse lung produced opposite effects on these parameters. Interleukin (IL)-6 did not alter basal airways resistance and decreased methacholine responsiveness, whereas IL-11 caused airways obstruction and increased airway responses to methacholine. To clarify these differences we examined histologic sections and used morphometry to compare bronchiolar and parenchymal dimensions in 1- to 2-mo-old transgenic mice expressing IL-6 or IL-11 and littermate control mice. Both transgenic strains showed similar emphysema-like airspace enlargement, nodular peribronchiolar collections of mononuclear cells, thickening of airway walls, and subepithelial airway fibrosis. When compared with littermate control mice, the IL-6 mice showed an approximately 50% increase in the caliber of their bronchioles and an increase in airway wall thickness that was in proportion to the increase in the size of their airways. In contrast, the remodeling response was more robust in the IL-11 transgenic mice. It was also seen in airways with normal external and luminal diameters and thus was out of proportion to the caliber of their airways. These results support the hypothesis that structural alterations and resulting caliber changes of respiratory airways can have important effects on airway physiology and reactivity.
Am J Respir Cell Mol Biol 2000 Mar
PMID:Airway hyperresponsiveness and airway obstruction in transgenic mice. Morphologic correlates in mice overexpressing interleukin (IL)-11 and IL-6 in the lung. 1069 65

The interleukin-11 receptor (IL-11R) belongs to the hematopoietic receptor superfamily. The functional receptor complex comprises IL-11, IL-11R and the signal-transducing subunit gp130. The extracellular part of the IL-11R consists of three domains: an N-terminal immunoglobulin-like domain, D1, and two fibronectin-type III-like (FNIII) domains and D2 and D3. The two FNIII domains comprise the cytokine receptor-homology region defined by a set of four conserved cysteine residues in the N-terminal domain (D2) and a WSXWS sequence motif in the C-terminal domain (D3). We investigated the structural and functional role of the third extracellular receptor domain of IL-11R. A molecular model of the human IL-11/IL-11R complex allowed the identification of amino acid residues in IL-11R to be involved in ligand binding. Most of them were located in the third extracellular domain, which therefore should be able to bind with high affinity to IL-11. To prove this prediction, domain D3 of the IL-11R was expressed in Escherichia coli, refolded and purified. For structural characterization, circular dichroism, fluorescence and NMR spectroscopy were used. By plasmon resonance experiments, we show that the ligand-binding capacity of this domain is as high as that one for the whole receptor. These results provide a basis for further structural investigations that could be used for the rational design of potential agonists and antagonists essential in human therapy.
J Mol Biol 2001 Feb 16
PMID:Identification of the domain in the human interleukin-11 receptor that mediates ligand binding. 1123 99

Interleukin (IL)-1beta induces cyclooxygenase (COX)-2 expression and prostanoid formation in cultured human airway smooth muscle (HASM) cells. In other cell types, IL-6 family cytokines induce COX-2 or augment IL-1beta-induced COX-2 expression. The purpose of this study was to determine whether IL-6 family cytokines were involved in COX-2 expression in HASM cells. RT-PCR was used to demonstrate that the necessary receptor components for IL-6-type cytokine binding are expressed in HASM cells. IL-6 and oncostatin M (OSM) each caused a dose-dependent phosphorylation of signal transducer and activator of transcription-3, whereas IL-11 did not. IL-6, IL-11, and OSM alone had no effect on COX-2 expression. However, OSM caused dose-dependent augmentation of COX-2 expression and prostaglandin (PG) E(2) release induced by IL-1beta. In contrast, IL-6 and IL-11 did not alter IL-1beta-induced COX-2 expression. IL-6 did increase IL-1beta-induced PGE(2) formation in unstimulated cells but not in cells stimulated with arachidonic acid (AA; 10(-5) M), suggesting that IL-6 effects were mediated at the level of AA release. Our results indicate that IL-6 and OSM are capable of inducing signaling in HASM cells. In addition, OSM and IL-1beta synergistically cause COX-2 expression and PGE(2) release.
Am J Physiol Lung Cell Mol Physiol 2001 Jun
PMID:Interleukin-6 family cytokines: signaling and effects in human airway smooth muscle cells. 1135 Aug 2

Stem cells from a variety of tissues have recently been shown to be capable of differentiating into cells characteristic of a separate tissue, apparently in response to microenvironmental signals. This is hierarchical plasticity. We have shown that both human and murine neurosphere cells with potential for differentiating into neurons, oligodendrocytes, and astrocytes can produce hematopoietic stem cells when engrafted into fetal sheep or murine day 3.5 blastocysts, respectively. We have also demonstrated an alternative form of stem cell plasticity: functional plasticity at different points in cell cycle transit and at different phases of a circadian rhythm. We have shown that long-term engraftment varies reversibly as primitive murine stem cells (lineage-negative rhodamine(low) Hoechst(low)) transit the cell cycle under stimulation by interleukin-3 (IL-3), IL-6, IL-11, and steel factor, with engraftment being defective in late S/early G2. Engraftment also varies markedly with circadian time. Presumptive mechanisms for these phenotypic shifts include alteration in adhesion protein expression with consequent changes in marrow homing. Most recently, we have also demonstrated that stem cell differentiation varies markedly with cell cycle transit. There are other features of the hematopoietic stem cell which suggest that it is a highly plastic cell with the ability to rapidly change its membrane phenotype, while exhibiting extraordinary directed motility. These data suggest that cell cycle and circadian plasticity should be considered additional major features of the hematopoietic stem cell phenotype.
Blood Cells Mol Dis
PMID:Physical and physiological plasticity of hematopoietic stem cells. 1178 58

Differentiation of endometrial stromal cells into decidual cells is crucial for embryo implantation and placentation. Interleukin (IL)-11 signalling is essential for adequate decidualization in the mouse uterus. We examined the role of IL-11 during progesterone-induced decidualization of human endometrial stromal cells over a 10-12 day period, using prolactin (PRL) production as a decidual marker. These cells produced biologically active IL-11 and expressed IL-11, IL-11Ralpha and PRL mRNA during decidualization. Neutralization of endogenous IL-11 with an anti-human (hu)IL-11 antibody (AB) reduced production of PRL from day 8 and insulin-like growth factor binding protein (IGFBP)-1, another marker of decidualization, from day 10 of culture. Following AB washout, PRL and IGFBP-1 secretion increased. Addition of recombinant (r)huIL-11 (10 or 100 ng/ml) to endometrial stromal cells increased secretion of PRL from day 4 and IGFBP-1 from day 6 compared with progesterone alone. Morphological signs of differentiation accompanied biochemical differentiation in the progesterone-treated cells and were further induced by exogenous rhuIL-11. Our observations demonstrate that human endometrial stromal cells produce biologically active IL-11, which promotes progesterone-induced decidualization. These results suggest that IL-11 has both paracrine and autocrine actions on human endometrial stromal cells and plays an important role in preparing the human endometrium for implantation.
Mol Hum Reprod 2002 Jul
PMID:Interleukin 11 advances progesterone-induced decidualization of human endometrial stromal cells. 1208 78

Interleukin (IL)-6, leukaemia inhibitory factor (LIF) and IL-11 belong to the same family of cytokines whose receptors utilize gp130 as the signalling molecule. We have investigated the expression of the IL-11 receptor, IL-11Ralpha, protein in the human endometrium in vivo and the effects of IL-6, LIF and IL-11 on the production of metalloproteinases (MMPs) and cytokines by cultured endometrial epithelial and stromal cells. Immunostaining showed that IL-11Ralpha was expressed in both epithelial and stromal cells, with epithelial staining being more intense than stromal staining and little variation in staining in either compartment throughout the cycle. Incubation of both stromal and epithelial cells with IL-6, LIF and IL-11 had no effect on MMP-2, -7, -9, transforming growth factor (TGF)beta or IL-1beta production or cell growth. IL-6 and LIF also had no effect on tumour necrosis factor (TNF)alpha production, but IL-11 caused a dose-dependent decrease in TNFalpha production by epithelial cells. IL-6 receptor, LIF receptor and gp130 were all expressed by cultured stromal and epithelial cells, showing that the lack of effect is not due to lack of expression of the receptor components. The results show that although IL-6, LIF and IL-11 signal through the same molecule, they may have different effects in endometrial cells, suggesting the activation of different signalling pathways, which may ultimately be important in the control of endometrial function.
Mol Hum Reprod 2002 Sep
PMID:Expression of interleukin (IL)-11 receptor by the human endometrium in vivo and effects of IL-11, IL-6 and LIF on the production of MMP and cytokines by human endometrial cells in vitro. 1220 Apr 62

Fibroblast apoptosis is crucial to the resolution of fibrosis. However, the mechanisms by which these cells undergo apoptosis are not well known. Because interleukin (IL)-6 and IL-11 may alter repair and remodeling processes, we hypothesized that they may play a role in idiopathic pulmonary fibrosis (IPF). We investigated the effects of these cytokines on Fas-induced apoptosis using primary lung fibroblasts from three patients with IPF (IPF-Fb) and three subjects without lung disease (normal-Fb). IPF-Fb were resistant to Fas-induced apoptosis compared with normal-Fb (P < 0.01). Using RNase protection assays, we showed that IL-6 enhanced Fas-induced apoptosis and expression of Bax in normal-Fb, but inhibited apoptosis and induced expression of Bcl-2 in IPF-Fb. Densitometry of Western blots revealed a Bcl-2/Bax ratio 0.15 +/- 0.01 in normal-Fb compared with 12.05 +/- 1.0 in IPF-Fb. Upregulation of Bcl-2 in normal-Fb and Bax in IPF-Fb were both STAT-3-dependent. Inhibition of extracellular signal-regulated kinase had no effect in normal-Fb, but reversed the antiapoptotic effect of IL-6 in IPF-Fb. IL-11 inhibited Fas-induced apoptosis and increased Bcl-2 expression in both normal-Fb and IPF-Fb. These results suggest that altered IL-6 signaling in IPF-Fb may enhance the resistance of these cells to apoptosis and contribute to a profibrotic effect of IL-6 in IPF.
Am J Respir Cell Mol Biol 2003 Oct
PMID:Inverse effects of interleukin-6 on apoptosis of fibroblasts from pulmonary fibrosis and normal lungs. 1271 76

Acute lung injury is a frequent and treatment-limiting consequence of therapy with 100% oxygen. Previous studies have determined that both interleukin (IL)-6 and IL-11 are protective in oxygen toxicity. This protection was associated with markedly diminished alveolar-capillary protein leak, endothelial and epithelial membrane injury, lipid peroxidation, and pulmonary neutrophil recruitment. Hyperoxia also caused cell death with DNA fragmentation in the lungs of transgene (-) animals, and both IL-6 and IL-11 markedly diminished this cell death response. However, the mechanism(s) by which these cytokines protect cells from death is unclear. In the present study, we characterized the effects of H2O2 on subconfluent human umbilical vein endothelial cell (HUVEC) and human pulmonary microvascular endothelial cell (HPMEC) cultures. We found that preincubation of HUVEC cultures with either IL-6 or IL-11 diminished H2O2 (1.0 mM)-induced cell death. Similar effects were noted with HPMEC showing that this effect is not HUVEC-specific. The protective effects of both IL-6 and IL-11 were not associated with any changes in antioxidants and were decreased by approximately 80% in the presence of U0126, a specific inhibitor of MEK-1-dependent pathways. The cytoprotective effects of IL-11 and IL-6 were also completely eliminated in STAT3 dominant-negative transduced HUVEC cultures. These studies demonstrate that IL-6 and IL-11 both confer cytoprotective effects that diminish oxidant-mediated endothelial cell injury. They also demonstrate that this protection is mediated, at least in part, by a STAT3 and MEK-1-dependent specific signal transduction pathway(s).
Am J Respir Cell Mol Biol 2003 Oct
PMID:Interleukin-11 and interleukin-6 protect cultured human endothelial cells from H2O2-induced cell death. 1273 73

The hematopoietic stem cell population, lineage negative-Sca positive (HSC), displays a homing defect into bone marrow (BM) after 48-h exposure to interleukin (IL)-3, IL-6, IL-11, and steel factor [J. Hematother. Stem Cell Res. 11 (2002) 913]. Cytokine treatment of murine marrow leads to reversible alterations in adhesion protein expression, which may explain the changes in homing. We evaluated 3 h homing to nonhematopoietic organs of marrow cells exposed to cytokines for 0, 18, 24, 40 and 48 h. HSC cells from C57BL/6J mice were cultured and labeled with the cytoplasmic fluorescent dye CFSE. We found homed events from uncultured cells in spleen, liver and lung, but no events were seen in duodenum or anterior tibialis muscle. Culture in cytokines led to decreased homing to marrow at 24 and 48 h with parallel changes in spleen homing. There was little variability of homing to liver, however the number, of homed events in lung was markedly increased when 24-h cultured cells were assessed. This was approximately a 10-fold increase compared to the 0 h time point (flow cytometry). Homing was determined by evaluation of frozen section (8 microm) by fluorescent microscopy for spleen, liver, duodenum, anterior tibialis and lung. Data were confirmed by flow cytometry from each organ including marrow. These data indicate the presence of a lung homing "hotspot" at 24 h of cytokine culture; this is a time when the stem progenitors cells are in mid S-phase. Altogether these data suggest that homing of marrow cell to nonmarrow organs may fluctuate with cell cycle transit and that there is a lung homing hotspot in mid-S.
Blood Cells Mol Dis
PMID:Homing and conversion of murine hematopoietic stem cells to lung. 1475 12

Embryo implantation and subsequent decidualization, trophoblast invasion and formation of a functional placenta are crucial for establishment and maintenance of pregnancy. Interleukin-11 signalling has been shown to be obligatory for adequate decidualization and trophoblast invasion in mice. Defects in IL-11 signalling in mice result in trophoblast over-invasion and fetal loss. The pathological situation of human tubal pregnancy resembles that of IL-11Ralpha(-/-) mice concerning these symptoms. As our interest is focused on the human early pregnancy, we compared IL-11 expression at the implantation site of ectopic tubal pregnancy (EP) to 1st and 2nd trimester of normal intrauterine pregnancies (IP), and to the normal cycling endometrium. The mRNA expression of IL-11 and IL-11Ralpha was analysed by semiquantitative RT-PCR. Protein expression was detected by western blotting and immunohistochemistry. IL-11Ralpha is expressed constitutively in all tissue specimens analysed. IL-11 is expressed predominantly during follicular and early luteal phase of the menstrual cycle. In IP, IL-11 expression peaks during the 1st trimester and declines from the beginning of the 2nd trimester onwards. In tubal abortions, IL-11 expression is reduced in comparison to vital EP and IP. Cultured primary endometrial and decidual epithelial cells were analysed for hormonal regulation of IL-11 by enzyme-linked immunosorbent assay and RT-PCR. IL-11 is up-regulated by estrogen and down-regulated by progesterone. Overall, our results indicate that in humans, IL-11 signalling is significantly involved in regulation of trophoblast invasion. In the case of tubal abortion, inadequate IL-11 signalling may therefore result in dysregulation of trophoblast invasion.
Mol Hum Reprod 2004 Nov
PMID:Interleukin-11 expression: its significance in eutopic and ectopic human implantation. 1546 50


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