REGULATION OF INSULIN LIKE GROWTH FACTOR I

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DESCRIPTION (Adapted from the applicant's abstract) The interstitial lung diseases are comprised of a large collection of heterogenous pulmonary disorders having in common an initial phase of inflammation followed by a phase of exuberant fibrosis. The inexorable fibrosis is paralleled by a course of relentless respiratory insufficiency. As a group, treatment of patients with these disorders have been largely disappointing. Alveolar macrophages play a vital role in idiopathic pulmonary fibrosis by secreting growth factors that are essential for fibroblast proliferation and activation. Of the many growth factors expressed by macrophages, insulin-like growth factor-I (IGF-1) has been strongly linked to the pathogenesis and progression of pulmonary fibrosis by stimulating fibroblasts to proliferate and to synthesize collagen. Previous work from this laboratory has shown that the expression of IGF-I is augmented by TNFalpha and is dramatically inhibited by IFNgamma at the transcriptional level in murine macrophages. The overall goal of this proposal is to determine the mechanism by which these two critical processes occur. Based on previous findings that TNFalpha is known to activate both the mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) and c-Jun kinase/stress-activated protein kinase (JNK/SAPK) signal transduction pathways (which can activate c-Fos and c-Jun, respectively) and that the IGF-I promoter contains a recognition site for the AP- I transcription factor (composed of either a homodimer of c-Jun or a heterodimer of c-Jun-c-Fos), we propose to test the hypothesis that the increased expression of IGF-I in response to TNFalpha is mediated by the joint activation of the MAPK/ERK and JNK/SAPK pathways which then enhance transcription of the IGF-I gene by the formation of the AP-1 transcription factor. Based on previous reports that the down-regulation of IGF-I expression by IFNY is not due to IGF-I MRNA instability but rather a process that requires active protein synthesis, we propose to test the hypothesis that IFNY silences IGF-I expression by inducing and/or activating repressor protein(s), the trans acting factor, that binds to the 5'-flanking region of the IGF-I gene, the cis-acting element. Based on the first hypothesis that the transcriptional enhancer complex AP- I is critical in IGF-I synthesis, we will test the hypothesis that components of AP-1, c-jun and c-Fos, will be found in increased abundance in the lungs of patients with pulmonary fibrosis.