Am. J. Respir. Cell Mol. Biol., Volume 25, Number 2, August, 2001 254-259

GM-CSF Increases AP-1 DNA Binding and Ref-1 Amounts in Human Alveolar Macrophages

Dawn M. Flaherty, Martha M. Monick, A. Brent Carter, Michael W. Peterson, and Gary W. Hunninghake

Department of Internal Medicine, University of Iowa College of Medicine and Veterans Administration Medical Center, Iowa City, Iowa

Alveolar macrophages have been implicated in the pathogenesis of a number of acute and chronic lung disorders. A characteristic feature of many of the chronic lung diseases is that the types of macrophages in the lung change, and in most instances, the cells resemble monocyte-like cells. We have previously shown that normal human alveolar macrophages have a decreased capacity to express protein kinase C (PKC)-induced DNA binding activity of the transcription factor activator protein (AP)-1 compared with monocytes. This decrease in AP-1 DNA binding appears to be due to a defect in redox regulation of AP-1 proteins via a decrease in the redox active protein Ref-1. The hypothesis for this study is that there are factors generated during the development of chronic lung disease that increase AP-1 DNA binding activity and Ref-1 production in human alveolar macrophages. We have focused specifically on granulocyte-macrophage colony-stimulating factor (GM-CSF) as a prototype mediator that can be released by alveolar macrophages and is related to the fibrotic process in the lung. We found that after a 24-h incubation with GM-CSF, AP-1 DNA binding was significantly increased in both unstimulated, interleukin (IL)-13, and phorbol myristate acetate (PMA)-stimulated alveolar macrophages and that there was a corresponding increase in Ref-1 protein by Western blot analysis in the PMA-stimulated group. This suggests that disease-related cytokines such as GM-CSF and IL-13 may modulate AP-1 DNA binding activity in alveolar macrophages.

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