The JNK are important for development and survival of macrophages.
We report in this study that activation of the JNK by the growth factor, CSF-1 is critical for macrophage development, proliferation, and survival. Inhibition of JNK with two distinct classes of inhibitors, the pharmacological agent SP600125, or the peptide D-JNKI1 resulted in cell cycle inhibition with an arrest at the G(2)/M transition and subsequent apoptosis. JNK inhibition resulted in decreased expression of CSF-1R (c-fms) and Bcl-x(L) mRNA in mature macrophages and repressed CSF-1-dependent differentiation of bone marrow cells to macrophages. Macrophage sensitivity to JNK inhibitors may be linked to phosphorylation of the PU.1 transcription factor. Inhibition of JNK disrupted PU.1 binding to an element in the c-fms gene promoter and decreased promoter activity. Promoter activity could be restored by overexpression of PU.1. A comparison of expression profiles of macrophages with 22 other tissue types showed that genes that signal JNK activation downstream of tyrosine kinase receptors, such as focal adhesion kinase, Nck-interacting kinase, and Rac1 and scaffold proteins are highly expressed in macrophages relative to other tissues. This pattern of expression may underlie the novel role of JNK in macrophages.
Himes
S Roy
SR
Cooperative Research Centre for Chronic Inflammatory Disease, Institute for Molecular Biosciences, University of Queensland, Brisbane, Australia.
Sester
David P
DP
Ravasi
Timothy
T
Cronau
Stephen L
SL
Sasmono
Tedjo
T
Hume
David A
DA
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D002454:Cell Differentiation; D002470:Cell Survival; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology* / Q000201:enzymology*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
D004247:DNA; D048031:JNK Mitogen-Activated Protein Kinases; D016173:Macrophage Colony-Stimulating Factor; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016186:Receptor, Macrophage Colony-Stimulating Factor; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1