title: IL-4 blocks M-CSF-dependent macrophage proliferation by inducing p21Waf1 in a STAT6-dependent way.
abstract: Macrophages are recruited from the blood stream to the inflammatory loci to carry out their functional activities. In an early phase of the cell cycle, macrophages become activated by Th1-type cytokines (i.e. IFN-gamma), thereby producing several factors (cytokines, NO, etc.) and developing pro-inflammatory activities. When bacteria and apoptotic bodies are removed, through the interaction with Th2-type cytokines (i.e. IL-4), macrophages become anti-inflammatory and repair damaged tissues. Incubation of bone-marrow-derived macrophages with IFN-gamma or IL-4 blocked their proliferation. While M-CSF withdrawal caused cell cycle arrest at the early G(1) phase, treatment of macrophages with IFN-gamma or IL-4 caused this arrest later, at the G(1)/S boundary. Proliferation arrest was not due to an induction of apoptosis. IFN-gamma and IL-4 induced the expression of the cyclin-dependent kinase (Cdk) inhibitor p21(Waf1). Using KO mice and iRNA experiments, we found that p21(Waf1)is required for IL-4- but not for IFN-gamma-dependent inhibition of macrophage proliferation. IL-4 inhibited M-CSF-dependent Cdk-2 and Cdk-4 activities, which are necessary for entry and passage through the S phase of the cell cycle. The signal transduction used to induce the expression of p21(Waf1)after interaction of IL-4 with the corresponding receptor was mediated by STAT6. Thus, IL-4 and IFN-gamma blocked M-CSF-induced macrophage proliferation through distinct mechanisms.
authors.affiliation: Institute for Research in Biomedicine, University of Barcelona, Barcelona, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Arpa
authors.forename: Annabel F
authors.initials: AF
authors.lastname: Valledor
authors.forename: Jorge
authors.initials: J
authors.lastname: Lloberas
authors.forename: Antonio
authors.initials: A
authors.lastname: Celada
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D015847:Interleukin-4 / Q000276:immunology* / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050800:STAT6 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology
chemical_list: D000998:Antiviral Agents; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015847:Interleukin-4; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma