ABSTRACT
CD137 (ILA/4-1BB), a member of the TNF receptor family, regulates activation, survival and proliferation of primary human monocytes. Here we compare the activities of lipopolysaccharide (LPS), a classical and potent monocyte activator to that of CD137. LPS is a more potent activator of monocytes, as evidenced by a stronger induction of the proinflammatory cytokine IL-8. However, CD137 could further increase maximal cytokine induction by LPS, which points to separate signaling pathways for LPS and CD137. Also, expression of myc was only induced by the combination of CD137 and LPS. Expression of macrophage colony-stimulating factor is induced more potently by CD137, but an additive effect is obtained by the combination of CD137 and LPS. Monocyte/macrophage survival and proliferation is only induced by CD137. LPS counteracts both activities of CD137 via activation induced cell death. While LPS has a role in activation of monocytes in innate immunity, the CD137 receptor/ligand system seems to deliver an activating signal to monocyte in acquired immunity.
Subject(s)
Lipopolysaccharides/pharmacology , Macrophage Activation/drug effects , Monocytes/cytology , Monocytes/drug effects , Receptors, Nerve Growth Factor/metabolism , Receptors, Tumor Necrosis Factor/metabolism , Antigens, CD , Apoptosis/drug effects , Cell Adhesion/drug effects , Cell Division/drug effects , Cell Survival/drug effects , Cells, Cultured , Gene Expression Regulation/drug effects , Genes, myc/genetics , Humans , Interleukin-8/metabolism , Macrophage Colony-Stimulating Factor/metabolism , Monocytes/immunology , Monocytes/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Nerve Growth Factor/antagonists & inhibitors , Receptors, Tumor Necrosis Factor/antagonists & inhibitors , Recombinant Fusion Proteins/metabolism , Signal Transduction/drug effects , Tumor Necrosis Factor Receptor Superfamily, Member 9ABSTRACT
Peripheral monocytes are short-lived and are replenished from hematopoietic stem cells whose proliferation is believed to be confined to the bone marrow. Human peripheral monocytes are assumed not to be able to proliferate. In this study we show that CD137 (ILA/4-1BB), a member of the tumor necrosis factor receptor family, induces a widespread and profound proliferation of human peripheral monocytes. Macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor are essential, but not sufficient for proliferation. Additional soluble autocrine factors induced by CD137 are required. Induction of proliferation is mediated via reverse signaling through a CD137 ligand, expressed constitutively by peripheral monocytes. The ability of CD137 to induce proliferation in human peripheral monocytes is not shared by any other known molecule.
Subject(s)
Mitosis/drug effects , Monocytes/pathology , Monocytes/physiology , Receptors, Nerve Growth Factor/physiology , Receptors, Tumor Necrosis Factor/physiology , Antigens, CD , Cell Division/drug effects , Cells, Cultured , Humans , Ligands , Macrophage Colony-Stimulating Factor/pharmacology , Monocytes/drug effects , Recombinant Proteins/pharmacology , Tumor Necrosis Factor Receptor Superfamily, Member 9ABSTRACT
CD95 (APO-1/Fas) and CD137 (ILA/4-1BB) are members of the tumour necrosis factor receptor family, and both are involved in induction of apoptosis in lymphocytes. Contrary to the case of CD95, apoptosis by CD137 is caused by cross-linking of the respective ligand rather than the receptor. Nothing is known so far about the mechanism of CD137-induced cell death. Here, we show that immobilized CD137 protein induces expression of CD95 in resting primary T and B lymphocytes. However, induction of apoptosis by CD137 is independent of CD95, because: (1) antagonistic anti-CD95 antibody fragments do not block CD137-induced apoptosis; and (2) CD137, but not anti-CD95, can induce apoptosis in resting lymphocytes.
Subject(s)
Apoptosis/immunology , Lymphocytes/immunology , Signal Transduction , fas Receptor/immunology , Antigens, CD , B-Lymphocytes/immunology , Blotting, Western , Cells, Cultured , Flow Cytometry , Fluorescent Antibody Technique , Humans , Lymphocyte Count , Receptors, Nerve Growth Factor/analysis , Receptors, Tumor Necrosis Factor/analysis , T-Lymphocytes/immunology , Tumor Necrosis Factor Receptor Superfamily, Member 9ABSTRACT
CD137 (ILA/4-1BB), a member of the tumor necrosis factor (TNF) receptor family, promotes adherence and prolongs survival of human peripheral monocytes. It induces a strong expression of macrophage colony-stimulating factor (M-CSF), an essential monocyte survival factor. Monocyte survival induced by CD137 is primarily mediated by M-CSF and to a lesser extent by granulocyte-macrophage colony-stimulating factor and IL-3. Survival and induction of M-CSF are mediated via reverse signaling through a CD137 ligand expressed constitutively by peripheral monocytes.
Subject(s)
Monocytes/cytology , Receptors, Nerve Growth Factor/physiology , Receptors, Tumor Necrosis Factor/physiology , Antigens, CD , Cell Adhesion/drug effects , Cell Survival/drug effects , Granulocyte-Macrophage Colony-Stimulating Factor/physiology , Humans , Interleukin-3/physiology , Macrophage Colony-Stimulating Factor/physiology , Recombinant Proteins/pharmacology , Tumor Necrosis Factor Receptor Superfamily, Member 9ABSTRACT
CD137 (ILA/4-1BB) is a member of the tumor necrosis factor receptor family and regulates activation, proliferation and programmed cell death in T lymphocytes. Here we show the existence of a soluble form of CD137 (sCD137) of 16 kDa. sCD137 is released by activated lymphocytes, and in contrast to membrane-bound CD137, expression of sCD137 seems to be restricted to lymphocytes. sCD137 is generated by alternative splicing and two splice variants were identified. sCD137 is present at low levels in sera of some healthy donors (5/12; mean = 0.18 ng/ml) and is significantly enhanced in sera of patients with rheumatoid arthritis (12/12; mean = 3.58 ng/ml).
Subject(s)
Arthritis, Rheumatoid/blood , Lymphocyte Activation , Lymphocytes/metabolism , Receptors, Nerve Growth Factor/blood , Receptors, Tumor Necrosis Factor/blood , Antigens, CD , Enzyme-Linked Immunosorbent Assay , Humans , Polymerase Chain Reaction , RNA Splicing , Receptors, Nerve Growth Factor/chemistry , Receptors, Nerve Growth Factor/genetics , Receptors, Tumor Necrosis Factor/chemistry , Receptors, Tumor Necrosis Factor/genetics , Solubility , Tumor Cells, Cultured , Tumor Necrosis Factor Receptor Superfamily, Member 9ABSTRACT
CD137 (ILA/4-1BB), a member of the TNF receptor family, was shown previously to inhibit proliferation and to induce apoptosis in T lymphocytes. In this study, we identify CD137 as a novel and potent monocyte activation factor. CD137 protein induces expression of IL-6, IL-8, and TNF-alpha, and inhibits expression of IL-10. Furthermore, CD137 differentially regulates expression of cell surface receptors. It induces expression of ICAM and reduces expression of FcgammaRIII, while levels of HLA-DR remain unchanged. CD137 also promotes adherence of monocytes. These effects of CD137 require immobilization of CD137 protein, indicating that they are mediated by cross-linking of a corresponding ligand/coreceptor expressed on monocytes.
Subject(s)
Monocytes/immunology , Receptors, Nerve Growth Factor/physiology , Receptors, Tumor Necrosis Factor/physiology , Signal Transduction/immunology , Antigens, CD , Binding, Competitive/immunology , Cell Adhesion/drug effects , Cell Adhesion/immunology , Cells, Cultured , Down-Regulation/immunology , Gene Expression Regulation , Humans , Interleukin-6/biosynthesis , Interleukin-8/biosynthesis , Interleukin-8/genetics , Monocytes/drug effects , Monocytes/metabolism , Polymerase Chain Reaction/methods , Receptors, IgG/antagonists & inhibitors , Receptors, IgG/biosynthesis , Receptors, Nerve Growth Factor/immunology , Receptors, Nerve Growth Factor/metabolism , Receptors, Tumor Necrosis Factor/immunology , Receptors, Tumor Necrosis Factor/metabolism , Signal Transduction/drug effects , Tumor Necrosis Factor Receptor Superfamily, Member 9 , Tumor Necrosis Factor-alpha/biosynthesisSubject(s)
Antibodies/chemistry , Cross Reactions , Immunoblotting/methods , Animals , Diagnostic Errors , Immunoblotting/adverse effects , Mice , Precipitin Tests , Protein Tyrosine Phosphatases/analysis , Protein Tyrosine Phosphatases/immunology , Sensitivity and Specificity , Species Specificity , Spleen/cytology , Spleen/immunologyABSTRACT
This study examined the immunoregulatory effects of cis-9,10-octadecenoamide (CODA), a recently identified endogenous sleep-inducing brain lipid. CODA displays structural and functional similarities to anandamide, the endogenous ligand for the cannabinoid receptors. CODA proved to be immunosuppressive. It inhibited proliferation of anti-CD3- and ConA-activated primary lymphocytes and proliferation of T- and B-cell lines. Complete inhibition occurred at concentrations of 100 microM. This effect was stereospecific, since the trans-stereo isomer of CODA did not inhibit proliferation at identical concentrations. A further control compound, octadecanamide, identical to cis-9,10-octadecenoamide, besides lacking the 9,10 carbon double bond, also did not affect proliferation. The antiproliferative effects of CODA occurred rapidly, since 24-h exposure to CODA was sufficient for complete inhibition of proliferation. CODA and anandamide worked synergistically in inhibiting lymphocyte proliferation. No significant effects of CODA on monocyte functions, as assessed by LPS-induced TNF alpha secretion, could be detected.
