Identification of CD137 as a potent monocyte survival factor

Langstein, Joachim; Schwarz, Herbert

doi:10.1002/jlb.65.6.829

Cited by 70 publications

(48 citation statements)

References 23 publications

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“…Binding of 4-1BB to B cells in the presence of anti-IgM antibodies also increases proliferation of mouse spleen B cells (45). Moreover, 4-1BB induces the expression of M-CSF in monocytes (33). In connection with these findings, we found in this study that G-10 column-eluted bone marrow cells expressed 4-1BBL and that r4-1BB led to the induction of M-CSF in bone marrow cells.…”

Section: Fig 8 4-1bb-induced Responses Of Bmm Cellssupporting

confidence: 74%

Infection-induced Up-regulation of the Costimulatory Molecule 4-1BB in Osteoblastic Cells and Its Inhibitory Effect on M-CSF/RANKL-induced in Vitro Osteoclastogenesis

Saito

Ohara

Hotokezaka

et al. 2004

Journal of Biological Chemistry

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Bacterial infection sometimes impairs bone metabolism. In this study, we infected the osteoblastic cell line MC3T3-E1 with Mycobacterium bovis bacillus CalmetteGué rin (BCG) and identified genes that were up-regulated in the BCG-infected cells by the suppression subtractive hybridization method. A gene encoding 4-1BB (CD137), a member of the tumor necrosis factor-␣ receptor family, was found to be one of the up-regulated genes. Up-regulation of 4-1BB was also observed by infection with Escherichia coli, Salmonella typhimurium, and Tuberculosis is an ancient disease but still ranks as one of the foremost killers of the 21st century. About one-third of the world's population is infected with Mycobacterium tuberculosis and more than two million people die annually from tuberculosis (1). Most tuberculosis cases are pulmonary, but the microorganism sometimes invades the central nervous system, the lymphatic system, and the musculoskeletal system, or is sometimes disseminated throughout the whole body. Mycobacterium infection in bones and joints presents ϳ10% of the extra-pulmonary cases (2). Vertebral osteomyelitis and osteitis also occur as a complication of vaccination with bacillus Calmette-Guérin (BCG) 1 or intravesical use of BCG (3, 4). Osteomyelitis and osteitis caused by M. tuberculosis or BCG infection sometimes lead to vertebral caries in some patients as a result of increased bone resorption.Bone is maintained by dynamic equilibrium between osteoblasts and osteoclasts in bone marrow cells. M. tuberculosis and BCG infection of bone alters this equilibrium, resulting in the loss of extracellular matrix and collapse of bone, especially vertebrae. Whether this bone resorption is attributable to direct effects of the bacteria on bone cells or infection-induced activation of inflammatory cells has not been clarified. However, a few studies have shown that mycobacterial antigens interfere with bone metabolism. Wax D, a mycobacterial cell wall peptidoglycan fragment-arabinogalactan-mycolic acid complex, induced reactive bone formation accompanied with osteomyelitis in Buffalo rats (5). Heat shock protein 10 of M. tuberculosis stimulates bone resorption in bone explanting cultures and induces osteoclast recruitment but inhibits proliferation of an osteoblast bone-forming cell line (6). The secreted protein MPB70 of BCG has significant homology with four repeat domains of osteoblast-specific factor 2/periostin (7). Epidemiological study suggests that MPB70-overproducing strains of BCG seem to be associated with an increased incidence of osteitis after BCG vaccination of neonates (7).Osteoblasts express various enzymatic markers such as alkaline phosphatase (ALP) and produce collagenous and noncol-

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Section: Fig 8 4-1bb-induced Responses Of Bmm Cellssupporting

confidence: 74%

Infection-induced Up-regulation of the Costimulatory Molecule 4-1BB in Osteoblastic Cells and Its Inhibitory Effect on M-CSF/RANKL-induced in Vitro Osteoclastogenesis

Saito

Ohara

Hotokezaka

et al. 2004

Journal of Biological Chemistry

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“…The engagement of 4-1BBL on APC or myeloid precursors by 4-1BB-Fc fusion proteins has been shown to enhance cytokine production by human macrophages and to increase monocyte differentiation and survival (51)(52)(53). Conversely, recent reports have suggested that signaling through 4-1BBL on murine myeloid precursors limits their differentiation to monocytes and dendritic cells (45,54).…”

Section: Discussionmentioning

confidence: 99%

Endogenous 4-1BB Ligand Plays a Critical Role in Protection from Influenza-Induced Disease

Lin

Sedgmen

Moraes

et al. 2009

The Journal of Immunology

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A critical issue during severe respiratory infection is whether it is the virus or the host response that does the most damage. In this study, we show that endogenous 4-1BBL plays a critical role in protecting mice from severe effects of influenza disease. During mild respiratory influenza infection in which virus is rapidly cleared, the inducible costimulatory receptor 4-1BB is only transiently induced on lung T cells and 4-1BB ligand (4-1BBL) is completely dispensable for the initial CD8 T cell response and mouse survival. In contrast, during more severe respiratory influenza infection with prolonged viral load, 4-1BB expression on lung CD8 T cells is sustained, and 4-1BBL-deficient mice show decreased CD8 T cell accumulation in the lungs, decreased viral clearance, impaired lung function, and increased mortality. Transfer of an optimal number of naive Ag-specific T cells before infection protects wild-type but not 4-1BBL-deficient mice from an otherwise lethal dose of influenza virus. T he CD8 T cells are important mediators of protective immunity to viruses (1). Indeed a strong CD8 T cell response to influenza offers the hope of cross-protective immunity to diverse influenza strains (2, 3). However, there is a concern that too strong an immune response in the lung will cause immune pathology and a worse outcome (4 -6). Upon initial encounter with Ag, T cells commit to programmed expansion, which occurs independently of the continued presence of Ag (7,8). How then does the immune system provide the appropriate level of T cell stimulation for a particular infection? T cells regulate their level of response by integrating signals from the Ag-specific receptor as well as from costimulatory, coinhibitory, and cytokine receptors which in turn influence the initiation, duration, and differentiation of the response (9 -12). The initial activation of T cells requires costimulatory signals from CD28, expressed on resting T cells. In addition, during an on-going immune response, other costimulatory receptors and ligands are up-regulated on the T cells and APCs (13-15). The question arises as to why so many costimulatory receptor ligand pairs have accumulated in the mammalian immune system. Here we provide evidence that the expression of one such costimulatory receptor, 4-1BB, is sustained in response to severe as compared with mild respiratory infection with influenza virus, thereby allowing the immune system to maintain a level of CD8 T cell response appropriate for the severity of the infection.The receptor 4-1BB (CD137) is a member of the TNFR family expressed on Ag-receptor activated T cells (14, 16 -18). In vivo with nonreplicating immunogens, 4-1BB is rapidly and transiently up-regulated on T cells upon immunization, before the first cell division and concomitantly with the expression of the early activation marker CD69 (19). Evidence that 4-1BB can play a role early in the response comes from systemic administration of agonist anti-4-1BB Abs, which can enhance initial antitumor and antiviral T cell responses wi...

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“…Total bone marrow cells cultured on immobilized CD137-Fc protein also had an increase in CD11b ϩ , CD14 ϩ , F4/80 ϩ , or CD11c ϩ cells, although mature myeloid cells such as monocytes and macrophages, among total bone marrow cells that are known to respond to CD137 ligand signals with survival and proliferation (19,20,22), may have contributed in that case (data not shown).…”

Section: Cd137 Ligand Signaling Induces Differentiation To Monocytic mentioning

confidence: 91%

CD137 Induces Proliferation of Murine Hematopoietic Progenitor Cells and Differentiation to Macrophages

Jiang

Chen

Schwarz

2008

The Journal of Immunology

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CD137 is a member of the TNFR family, and reverse signaling through the CD137 ligand, which is expressed as a cell surface transmembrane protein, costimulates or activates APCs. CD137 and CD137 ligand are expressed on small subsets of bone marrow cells. Activation of bone marrow cells through CD137 ligand induces proliferation, colony formation and an increase in cell numbers. Compared with total bone marrow cells, the small subpopulation of progenitor cells that express no lineage markers but express CD117 cells (or Lin−, CD117+ cells) responds with the same activities to CD137 ligand signaling, but at a significantly enhanced rate. Concomitantly to proliferation, the cells differentiate to CFU granulocyte-macrophage and CFU macrophage, and then to monocytes and macrophages but not to granulocytes or dendritic cells. Hematopoietic progenitor cells differentiated in the presence of CD137 protein display enhanced phagocytic activity, secrete high levels of IL-10 but little IL-12 in response to LPS, and are incapable of stimulating T cell proliferation. These data demonstrate that reverse CD137 ligand signaling takes place in hematopoietic progenitor cells, in which it induces proliferation, an increase in cell numbers, colony formation, and differentiation toward monocytes and macrophages.

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Identification of CD137 as a potent monocyte survival factor

Cited by 70 publications

References 23 publications

Infection-induced Up-regulation of the Costimulatory Molecule 4-1BB in Osteoblastic Cells and Its Inhibitory Effect on M-CSF/RANKL-induced in Vitro Osteoclastogenesis

Infection-induced Up-regulation of the Costimulatory Molecule 4-1BB in Osteoblastic Cells and Its Inhibitory Effect on M-CSF/RANKL-induced in Vitro Osteoclastogenesis

Endogenous 4-1BB Ligand Plays a Critical Role in Protection from Influenza-Induced Disease

CD137 Induces Proliferation of Murine Hematopoietic Progenitor Cells and Differentiation to Macrophages

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