| Insulin-like Growth Factor-I (IGF-I) is a soluble polypeptide growth factor that we have found elevated in the lungs of individuals with fibroproliferative acute respiratory distress syndrome (FP-ARDS). IGF-I contributes to the fibroproliferative process in the lungs of individuals with FP-ARDS evidenced by positive correlations between enhanced IGF-I protein and each of collagen III and Proliferating Cell Nuclear Antigen, a marker of dividing cells, in alveolar epithelial lining fluids and lung biopsy specimens. Macrophages in the lungs of individuals with FP-ARDS contain IGF-I protein by immunohistochemical analysis and IGF-I mRNA detected by reverse transcription polymerase chain reaction, suggesting macrophages are a source of IGF-I in the lung. We sought to determine the molecular mechanism of IGF-I production in macrophages. Tumor Necrosis Factor, a pro-inflammatory cytokine that is also elevated in the lungs of individuals with FP-ARDS, stimulated an increased level of IGF-I mRNA in murine bone marrow derived macrophages in vitro, suggesting TNF may stimulate increased IGF-I production. We show that mitogen activated protein kinase intracellular signal transduction pathways including Erk, JNK and p38 participate in TNF induced IGF-I mRNA production in murine bone marrow derived macrophages. Further, use of a 1711 base pair rat I4GF-I promoter:luciferase reporter construct showed that the IGF-I promoter is transcriptionally active in murine macrophage cell lines, though this regulatory region showed no TNF-stimulated activity. Therefore, we cloned and sequenced a putative 1829 base pair regulatory region upstream of the murine IGF-I exon 1 translational start site. This murine IGF-I region contains potential transcriptional regulatory elements, though we were unable to show functional activity in transfected systems. These studies provide a better understanding of the regulation of IGF-I production in macrophages and a potential role of IGF-I production in the lungs of individuals with FP-ARDS. |
