Oncostatin M Production by Human Dendritic Cells in Response to Bacterial Products

Suda, Takafumi; Chida, Kingo; Todate, Akihito; Ide, Kyotaro; Asada, Kazuhiro; Nakamura, Yutaro; Suzuki, Kazutoshi; Kuwata, Hirofumi; Nakamura, Hirotoshi

doi:10.1006/cyto.2002.1023

Cited by 70 publications

(59 citation statements)

References 26 publications

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“…Indeed, OSM pretreatment of the footpads resulted in enhanced trafficking of labeled-BMDC to the draining LN. DC have been reported to be a source of OSM production (16), and our results confirm that DC stimulated with LPS (a TLR-4 agonist) increase OSM expression at both the mRNA and protein levels, implicating TLR activation as a molecular trigger for OSM production (16). By contrast, we show that TNF-␣ had no direct effect on OSM production by BMDC.…”

Section: Discussionsupporting

confidence: 80%

Oncostatin M Enhances CCL21 Expression by Microvascular Endothelial Cells and Increases the Efficiency of Dendritic Cell Trafficking to Lymph Nodes

Sugaya

Fang

Cardones

et al. 2006

The Journal of Immunology

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CCL21, a lymphatic endothelial cell (LEC)-derived chemokine, and its receptor CCR7 regulate dendritic cell (DC) trafficking to lymph nodes (LN), but it is unclear how CCL21 expression is regulated. Oncostatin M (OSM) is an IL-6-like cytokine synthesized by activated DC and other leukocytes. In vitro, OSM (but not TNF-α) stimulated CCL21 mRNA and protein expression by human dermal microvascular EC (DMEC) in an ERK1/2-dependent fashion. Conditioned medium from OSM-treated DMEC stimulated CCL21-dependent chemotaxis of mouse bone marrow-derived DC (BMDC). Cultured BMDC expressed OSM, which was increased with the addition of LPS. Topical application of the contact-sensitizing hapten, trinitrochlorobenzene, resulted in enhanced OSM expression in the skin, whereas cutaneous injection of TNF-α did not. Injection of OSM into the footpad increased CCL21 mRNA expression in the draining LN by ∼10-fold and in mouse skin by ∼4-fold without increasing CCR7 mRNA. In vitro, OSM increased the permeability of DMEC and lung microvascular EC monolayers to FITC-dextran beads, and, in vivo, it enhanced accumulation of Evans blue dye in draining LN by ∼3-fold (p = 0.0291). Of note, OSM increased trafficking of BMDC injected in footpads to draining LN by 2-fold (p = 0.016). In summary, OSM up-regulates CCL21 expression in skin and draining regional LN. We propose that OSM is a regulator of CCL21 expression and endothelial permeability in skin, contributing to efficient migration of DC to regional LN.

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Section: Discussionsupporting

confidence: 80%

Oncostatin M Enhances CCL21 Expression by Microvascular Endothelial Cells and Increases the Efficiency of Dendritic Cell Trafficking to Lymph Nodes

Sugaya

Fang

Cardones

et al. 2006

The Journal of Immunology

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“…OSM is produced by activated monocyte, T lymphocyte, and dendritic cell types and is also described as a potent inducer of inflammation (3)(4)(5)(6)(7)(8). OSM belongs to the interleukin-6 cytokine family also encompassing IL-11, IL-27, leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin-1, cardiotrophin-like cytokine, and neuropoietin (9 -12).…”

Section: Oncostatin M (Osm)mentioning

confidence: 99%

Molecular and Functional Characterization of a Soluble Form of Oncostatin M/Interleukin-31 Shared Receptor

Diveu¹,

Véneréau

Froger

et al. 2006

Journal of Biological Chemistry

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Activation of the signaling transduction pathways mediated by oncostatin M (OSM) requires the binding of the cytokine to either type I OSM receptor (leukemia inhibitory factor receptor/ gp130) or to type II OSM receptor (OSMR/gp130). In the present work we have developed an enzyme-linked immunosorbent assay detecting a soluble form of OSMR (sOSMR) secreted by glioblastoma, hepatoma, and melanoma tumor cell lines. sOSMR was also present in sera of healthy individuals, with increased levels in multiple myeloma. Molecular cloning of a corresponding cDNA was carried out, and it encoded for a 70-kDa protein consisting of a half cytokine binding domain containing the canonical WSXWS motif, an immunoglobulinlike domain, and the first half of a second cytokine binding domain with cysteines in fixed positions. Analysis of the soluble receptor distribution revealed a preferential expression in lung, liver, pancreas, and placenta. sOSMR was able to bind OSM and interleukin-31 when associated to soluble gp130 or soluble interleukin-31R, respectively, and to neutralize both cytokine properties. We have also shown that OSM could positively regulate the synthesis of its own soluble receptor in tumor cells. Oncostatin M (OSM)3 was originally isolated from culture supernatant of U937 histiocytic leukemia cells based on its ability to inhibit the proliferation of the A375 melanoma cell line (1, 2). OSM is produced by activated monocyte, T lymphocyte, and dendritic cell types and is also described as a potent inducer of inflammation (3)(4)(5)(6)(7)(8). OSM belongs to the interleukin-6 cytokine family also encompassing IL-11, IL-27, leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin-1, cardiotrophin-like cytokine, and neuropoietin (9 -12).The cytokines of the IL-6 family use two-or three-membrane subunit receptors to form high affinity receptor complexes able to mediate downstream signaling events (13-14). These receptors belong to the type I cytokine receptors, characterized by the presence of at least one cytokine binding domain (CBD) with conserved cysteine positions and a WSXWS motif (15). All the receptor complexes belonging to the IL-6 cytokine family share the common gp130 signaling receptor subunit in the formation of their multimeric receptors (16). Depending on the ligand, gp130 can either homodimerize in the presence of IL-6 or IL-11 (17, 18) or heterodimerize with related type I cytokine receptors such as LIFR, IL-27R, or OSMR when recruited by other members of the IL-6 family of cytokines (19 -21).In humans, OSM signal transduction occurs via two distinct receptor complexes. The type I OSM receptor consists of the low affinity chain, LIFR, associated to gp130 (19). This type I receptor can indifferently bind LIF or OSM. Through this mechanism, OSM elicits biological activities overlapping with those induced by LIF, such as hepatocyte activation, bone renewal, or the in vitro maintenance of embryonic stem cell phenotype (22).The type II OSM receptor, specifically recognizing OSM, associa...

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“…We showed previously that the lack of OSM signaling causes altered bone marrow microenvironment [3,4]. As OSM is also produced by Th1 cells and DC [5][6][7][8], OSM is suggested to play a role in immune reactions. In fact, OSM from activated DC regulates CCL21 expression in microvascular endothelial cells and promotes the trafficking of DC to LN [8].…”

Section: Introductionmentioning

confidence: 98%

Oncostatin M deficiency leads to thymic hypoplasia, accumulation of apoptotic thymocytes and glomerulonephritis

et al. 2009

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Oncostatin M (OSM) has been implicated in immune regulation, though its precise role remains elusive. Here we show that OSM plays a crucial role in the prevention of autoimmune diseases. OSM-deficient mice showed normal development of T cells, B cells and DC; however, their thymus showed hypoplasia and altered medullary structure. Autoantibodies against dsDNA accumulated and glomerulonephritis developed in aged OSMdeficient mice. Apoptotic cells accumulated in the thymus of OSM-deficient mice, and the administration of dexamethasone in young OSM-deficient mice resulted in the massive accumulation of apoptotic thymocytes and production of autoantibodies. These results suggest that OSM plays a key role in the prevention of autoimmune disease by regulating the clearance of apoptotic thymocytes.Key words: Apoptosis . Autoimmunity . Phagocytosis Supporting Information available online IntroductionOncostatin M (OSM) is a member of the IL-6 family of cytokines, and the OSM receptor (OSMR) consists of gp130 and the OSMRb subunit [1]. OSM is produced by a variety of cells including hematopoietic cells and fibroblasts, and is involved in various biological systems [2]. We showed previously that the lack of OSM signaling causes altered bone marrow microenvironment [3,4]. As OSM is also produced by Th1 cells and DC [5][6][7][8], OSM is suggested to play a role in immune reactions. In fact, OSM from activated DC regulates CCL21 expression in microvascular endothelial cells and promotes the trafficking of DC to LN [8].Moreover, Tg mice that express OSM using the lck proximal promoter exhibit thymic hypertrophy [9,10], suggesting that OSM may play a role in T-cell development within the thymic environment.Apoptosis is an essential process for development and homeostasis and defective clearance of apoptotic cells can lead to production of autoantibody by releasing cell debris, breaking peripheral tolerance. Macrophages in various tissues play an essential role in the elimination of apoptotic cells by phagocytosis. A vast majority of thymocytes are depleted by apoptosis during T-cell selections; however, apoptotic cells are barely detected in the thymus, indicating the presence of a mechanism to eliminate apoptotic thymocytes. Dying cells are normally removed rapidly from tissues by phagocytes, without eliciting inflammatory or immune responses. Clearance of apoptotic cells is crucial for prevention of autoimmune diseases [11,12] 1664with impaired macrophage phagocytosis exhibit splenomegaly due to accumulation of massive quantities of apoptotic cells and such defect in humans leads to retinitis pigmentosa [13].Previously, we demonstrated that OSM induces the development of thymic macrophages with strong phagocytic activity from intrathymic progenitors via OSM-responsive thymic epithelial cells (TEC) [14,15]. In this report, we show that OSM deficiency resulted in thymic hypoplasia, defective clearance of apoptotic thymocytes, accumulation of autoantibody and glomerulonephritis. Administration of dexamethasone (Dex) in OSM-defi...

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Oncostatin M Production by Human Dendritic Cells in Response to Bacterial Products

Cited by 70 publications

References 26 publications

Oncostatin M Enhances CCL21 Expression by Microvascular Endothelial Cells and Increases the Efficiency of Dendritic Cell Trafficking to Lymph Nodes

Oncostatin M Enhances CCL21 Expression by Microvascular Endothelial Cells and Increases the Efficiency of Dendritic Cell Trafficking to Lymph Nodes

Molecular and Functional Characterization of a Soluble Form of Oncostatin M/Interleukin-31 Shared Receptor

Oncostatin M deficiency leads to thymic hypoplasia, accumulation of apoptotic thymocytes and glomerulonephritis

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