IL-4 blocks M-CSF-dependent macrophage proliferation by inducing p21Waf1 in a STAT6-dependent way.
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.
Arpa
Luis
L
Institute for Research in Biomedicine, University of Barcelona, Barcelona, Spain.
Valledor
Annabel F
AF
Lloberas
Jorge
J
Celada
Antonio
A
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
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