CD137 ligand-mediated reverse signals increase cell viability and cytokine expression in murine myeloid cells: involvement of mTOR/p70S6 kinase and Akt.
Cross-linking of CD137 ligand (CD137L), a member of the TNF family, with recombinant CD137-Fc (rCD137-Fc) protein enhanced adherence of bone marrow-derived macrophages, and increased the expression of ICAM-1, IL-1beta, IL-6, M-CSF and phosphotyrosine proteins. In RAW264.7 cells, a murine myeloid cell line, rCD137-Fc not only increased adherence but also cell multiplication, in a manner comparable to LPS or M-CSF. In addition, it up-regulated expression of IL-1beta, IL-1 receptor antagonist, IL-6, COX2, tenascin C, neuropeptide Y and M-CSF mRNA. Neutralization of M-CSF by incubating the RAW264.7 cells with anti-M-CSF mAb did not prevent the CD137L signal-induced viability. Viability was blocked by PP2, an Src tyrosine kinase inhibitor, rapamycin, an mTOR inhibitor and LY294002, a PI3K inhibitor, but not by Wortmannin, another PI3K inhibitor. Cross-linking of CD137L increased phosphorylation of Akt and p70S6 kinase. The latter was blocked by PP2, rapamycin or LY294002, but not by Wortmannin, whereas phosphorylation of Akt was blocked by LY294002 or Wortmannin. These findings demonstrate that reverse signals evoked by CD137L regulate immune functions in macrophages.
Kim
Dong-Ku
DK
Graduate School of Life Science and Biotechnology, Pochon CHA University, CHA Stem Cell Institute, Seoul, Korea.
Lee
Sang Chul
SC
Lee
Hyeon-Woo
HW
D053330:4-1BB Ligand / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology*; D002867:Chromones / Q000494:pharmacology; D016207:Cytokines / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007113:Immunity, Innate; D007166:Immunosuppressive Agents / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009025:Morpholines / Q000494:pharmacology; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism
D053330:4-1BB Ligand; C412373:AG 1879; D002352:Carrier Proteins; D002867:Chromones; D016207:Cytokines; D004791:Enzyme Inhibitors; C090509:Icam1 protein, mouse; D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009025:Morpholines; D011743:Pyrimidines; D011994:Recombinant Proteins; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D018799:Intercellular Adhesion Molecule-1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D016173:Macrophage Colony-Stimulating Factor; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus