Etl2, A Novel Putative Type-I Cytokine Receptor Expressed during Mouse Embryogenesis at High Levels in Skin and Cells with Skeletogenic Potential

Neuhaus, Herbert; Bettenhausen, Berthold; Bilinski, Petra; Simon-Chazottes, Dominique; Guénet, Jean-Louis; Gossler, Achim

doi:10.1006/dbio.1994.1335

Cited by 34 publications

(37 citation statements)

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“…Consistent with the wide spectrum of IL-11 activities, IL-11R transcripts were detected in numerous tissues and cell types, including the decidua on the ninth day of pregnancy (Neuhaus et al 1994). Here we report that signals mediated by the IL-11R␣ are specifically required for normal female reproduction.…”

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confidence: 61%

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Maternal IL-11Rα function is required for normal decidua and fetoplacental development in mice

Bilinski

Roopenian²,

Gossler³

1998

Genes Dev.

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178

108

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In eutherian mammals, implantation and establishment of the chorioallantoic placenta are essential for embryo development and survival. As a maternal response to implantation, uterine stromal cells proliferate, differentiate, and generate the decidua, which encapsulates the conceptus and forms the maternal part of the placenta. Little is known about decidual functions and the molecular interactions that regulate its development and maintenance. Here we show that the receptor for the cytokine interleukin-11 (IL-11R␣) is required specifically for normal establishment of the decidua. Females homozygous for a hypomorphic IL-11R␣ allele are fertile and their blastocysts implant and elicit the decidual response. Because of reduced cell proliferation, however, only small deciduae form. Mutant deciduae degenerate progressively, and consequently embryo-derived trophoblast cells generate a network of trophoblast giant cells but fail to form a chorioallantoic placenta, indicating that the decidua is essential for normal fetoplacentation. IL-11R␣ is expressed in the decidua as well as in numerous other tissues and cell types, including the ovary and lymphocytes. The differentiation state and proliferative responses of B and T-lymphocytes in mutant females were normal, and wild-type females carrying IL-11R␣ mutant ovaries had normal deciduae, suggesting that the decidualization defects do not arise secondarily as a consequence of perturbed IL-11R␣ signaling defects in lymphoid organs or in the ovary. Therefore, IL-11R␣ signaling at the implantation site appears to be required for decidua development.

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confidence: 61%

“…For Northern blot analysis 2-5 µg of poly(A) + RNA were electrophoresed and transferred to nylon membranes as described (Lehrach et al 1977;Sambrook et al 1989). Filters were hybridized as described (Neuhaus et al 1994).…”

Section: Rna Isolation and Northern Blot Analysismentioning

confidence: 99%

Maternal IL-11Rα function is required for normal decidua and fetoplacental development in mice

Bilinski

Roopenian²,

Gossler³

1998

Genes Dev.

Self Cite

178

108

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“…As a consequence, soluble extracytoplasmic forms of IL-6R␣ and CNTFR␣ potentiate cytokine activity because they allow signaling-competent ␤-chain dimers to be formed also in cells that do not naturally express membrane-bound ␣-chains (23,25). Recently, a murine IL-11 receptor ␣-chain was also cloned (26,27), followed by the molecular identification of its human counterpart (28,29). IL-11R␣ shares substantial sequence and structural similarities with IL-6R␣ and CNTFR␣, suggesting functional equivalence of this receptor chain in IL-11 biological activity and signaling activation.…”

mentioning

confidence: 99%

Functional Expression of Soluble Human Interleukin-11 (IL-11) Receptor α and Stoichiometry of in Vitro IL-11 Receptor Complexes with gp130

Neddermann¹,

Graziani²,

Ciliberto³

et al. 1996

Journal of Biological Chemistry

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The interleukin-6 (IL-6) family of cytokines activates signaling through the formation of either gp130 homodimers, as for IL-6, or gp130-leukemia inhibitory factor receptor (LIFR) heterodimers as for ciliary neurotrophic factor (CNTF), leukemia inhibitory factor, oncostatin M , and cardiotrophin-1. Recent in vitro studies with IL-6 and CNTF have demonstrated that higher order hexameric receptor complexes are assembled in which signaling chain dimerization is accompanied by the dimerization of both the cytokine molecule and its specific receptor ␣ subunits (IL-6R␣ or CNTFR␣, respectively). IL-11 is a member of the IL-6 family and known to require gp130 but not LIFR for signaling. In this study we investigate the functional and biochemical composition of the IL-11 receptor complex. The human IL-11 receptor ␣-chain was cloned from a human bone marrow cDNA library. IL-11R␣ was shown to confer IL-11 responsiveness to human hepatoma cells either by cDNA transfection or by adding a soluble form of the receptor (sIL11R␣) expressed in the baculovirus system to the culture medium. In vitro immunoprecipitation experiments showed that sIL11R␣ specifically binds IL-11 and that binding is enhanced by gp130. Similarly to IL-6 and CNTF, gp130 is able to induce dimerization of the IL-11•IL-11R␣ subcomplex, the result of which is the formation of a pentameric receptor complex. However, in contrast to the other two cytokines, IL-11 was unable to induce either gp130 homodimerization or gp130/LIFR heterodimerization. These results strongly suggest that an as yet unidentified receptor ␤-chain is involved in IL-11 signaling.

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“…5,16,17 Primary amino acid comparisons indicate that IL-11R␣ is most closely related to IL-6R␣ chain (24% amino acid homology) and CNTF receptor ␣ chain (22% amino acid homology). The extracellular domain contains structural features characteristic of hematopoietic receptors such as proline residues preceding each 100 amino acid subdomain, a motif of four conserved cysteines and one tryptophan residue, a series of polar and hydrophobic amino acid residues, and the WSXWS domain between the cysteine and transmembrane domain.…”

Section: Il-11 Receptormentioning

confidence: 99%

True

1999

Leukemia

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Interleukin 11 (IL-11) is a pleiotropic cytokine with biological activities on many different cell types. Recombinant human IL-11 (rhIL-11) is produced by recombinant DNA technology in Escherichia coli. Both in vitro and in vivo, rhIL-11 has shown effects on multiple hematopoietic cell types. Its predominant in vivo hematopoietic activity is the stimulation of peripheral platelet counts in both normal and myelosuppressed animals. This activity is mediated through effects on both early and late progenitor cells to stimulate megakaryocyte differentiation and maturation. rhIL-11 has been approved for the treatment of chemotherapy-induced thrombocytopenia. The hematopoietic effects of rhIL-11 are most likely direct effects on progenitor cells and megakaryocytes in combination with other cytokines or growth factors. rhIL-11 also induces secretion of acute phase proteins (ferritin, haptoglobin, C-reactive protein, and fibrinogen) from the liver. The induction of heme oxidase and inhibition of several P450 oxidases have been reported from in vitro studies. In vivo, rhIL-11 treatment decreases sodium excretion by the kidney by an unknown mechanism and induces hemodilution. rhIL-11 also exhibits anti-inflammatory effects in a variety of animal models of acute and chronic inflammation, including inflammatory bowel disease, inflammatory skin disease, autoimmune joint disease, and various infection-endotoxemia syndromes. rhIL-11 has trophic effects on non-transformed intestinal epithelium under conditions of mucosal damage. The mechanism of the anti-inflammatory activity of rhIL-11 has been extensively studied. rhIL-11 directly affects macrophage and T cell effector function. rhIL-11 inhibits tumor necrosis factor-alpha (TNF␣), interleukin 1␤ (IL-1␤), interleukin 12 (IL-12), interleukin 6 (IL-6), and nitric oxide (NO) production from activated macrophages in vitro. The inhibition of cytokine production was associated with inhibition of nuclear translocation of the transcription factor, nuclear factor kappa B (NF-B). The block to NF-B nuclear translocation correlates with the ability of rhIL-11 to maintain or enhance production of the inhibitors of NF-B, IB-␣ and IB-␤. In addition to effects on macrophages, rhIL-11 also reduces CD4 ؉ T cell production of Th1 cytokines, such as IFN␥ induced by IL-12, while enhancing Th2 cytokine production. rhIL-11 also blocks IFN␥ production in vivo. The molecular effects of rhIL-11 have also been studied in a clinical trial. Molecular analysis of skin biopsies of patients with psoriasis before and during rhIL-11 treatment demonstrates a decrease in mRNA levels of TNF␣, IFN␥ and iNOS. These activities suggest that in addition to its thrombopoietic clinical use, rhIL-11 may also be valuable in the treatment of inflammatory diseases. The clinical utility of the anti-inflammatory properties of rhIL-11 is being investigated in patients with Crohn's disease, psoriasis and rheumatoid arthritis. These diseases are believed to be initiated and maintained by activated CD4 ؉ Th1 cells in conjunction w...

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Etl2, A Novel Putative Type-I Cytokine Receptor Expressed during Mouse Embryogenesis at High Levels in Skin and Cells with Skeletogenic Potential

Cited by 34 publications

References 0 publications

Maternal IL-11Rα function is required for normal decidua and fetoplacental development in mice

Maternal IL-11Rα function is required for normal decidua and fetoplacental development in mice

Functional Expression of Soluble Human Interleukin-11 (IL-11) Receptor α and Stoichiometry of in Vitro IL-11 Receptor Complexes with gp130

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