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The c-Jun N-terminal kinases are important for development and survival of macrophages
S. Roy Himes, David P. Sester, Timothy Ravasi, Stephen L. Cronau, Tedjo Sasmono, and David A. Hume*.
CRC for Chronic Inflammatory Disease, Institute for Molecular Biosciences, University of Queensland, Brisbane, Australia 4072
*Address for correspondence:
Prof. D. A. Hume
Institute for Molecular Biosciences
Queensland Biosciences Precinct
Bldg. 80, Services Rd.
University of Queensland
Brisbane, Queensland
Australia 4072
Telephone: 61-7-3346-2074
Facsimile: 61-7-3346
Abstract:
We report here that activation of the c-Jun N-terminal kinases (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 G2/M transition and subsequent apoptosis. JNK inhibition resulted in decreased expression of CSF-1 receptor (c-fms) and Bcl-XL 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 kinsase (FAK), Nck interacting kinase (NIK), 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.
Running title: Jun kinases regulate macrophage development and survival
Keywords:
monocyte/macrophage, cytokine receptors, apoptosis, signal transduction |
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