Cyclophilin A is required for M-CSF-dependent macrophage proliferation.
The immunosuppressor sanglifehrin A (SfA) is a member of a family of immunophilin cyclophilin A-binding molecules and does not inhibit calcineurin activity. Sanglifehrin A inhibits M-CSF-dependent macrophage proliferation by arresting the G1 phase of the cell cycle but does not affect cell viability. This immunosuppressor exerts its action on proliferation by inactivating cyclin-dependent kinase 2 (Cdk2) activity. Moreover, c-myc expression is also repressed. In the early steps of M-CSF signaling, SfA inhibits the phosphorylation of Raf-1 and the external regulated kinases (ERK)1/2 and mitogen-activated protein kinase phosphatase-1, which are required for proliferation. The effects of SfA are not related to a block of the proteosome activity. These data show that immunophilin contributes to M-CSF-dependent proliferation through activation of the Raf-1/MEK/ERK pathway and the regulation of Cdk activities, which is required for cell cycle progression.
Sànchez-Tilló
Ester
E
Macrophage Biology Group, Institute for Research in Biomedicine, Barcelona Science Park, University of Barcelona, Barcelona, Spain.
Wojciechowska
Marta
M
Comalada
Monica
M
Farrera
Consol
C
Lloberas
Jorge
J
Celada
Antonio
A
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2 / Q000187:drug effects; D021984:Cyclophilin A / Q000276:immunology* / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects; D007783:Lactones / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation / Q000187:drug effects; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000187:drug effects; D020598:Proto-Oncogene Proteins c-myb / Q000187:drug effects; D019908:Proto-Oncogene Proteins c-raf / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013141:Spiro Compounds / Q000494:pharmacology
D018797:Cell Cycle Proteins; D007783:Lactones; D020598:Proto-Oncogene Proteins c-myb; D013141:Spiro Compounds; C121329:sanglifehrin A; D016173:Macrophage Colony-Stimulating Factor; D019908:Proto-Oncogene Proteins c-raf; D051357:Cyclin-Dependent Kinase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases; D021984:Cyclophilin A