The excessive accumulation of collagen is the hallmark of idiopathic pulmonary fibrosis (IPF). The knowledge of the factors and mechanisms that limit the production of collagen are central to our understanding of the normal balance of matrix deposition and pathologic fibrosis. We demonstrated that interleukin 1beta, (IL-1beta) tumor necrosis factor alpha (TNFalpha) and prostaglandins (PG) reduce the production of type I collagen by normal (NL) human lung fibroblasts by transcriptional regulation. We have preliminary evidence of an altered response of lung fibroblasts from patients with IPF to these cytokines in terms of collagen and PG production. The elements involved in the inhibition of the transcription of the type I procollagen genes by IL-1beta, TNFalpha, and PG have not been defined. The hypothesis to be tested here is that there is a defective regulation of the expression of the alpha(I) procollagen gene by IL-1beta, TNFalpha, and PG in IPF fibroblasts. To test this hypothesis we will pursue 3 main objectives: First, we will further define the participation of endogenous PG on IL-1beta, TNFalpha: and transforming growth factor beta1 (TGFbeta1) effects on collagen gene expression in IPF fibroblasts at the protein, mRNA, and transcriptional levels; second, we will identify cis- and trans-acting elements involved IL-1beta, TNFalpha and PG down-regulation of transcription of the alpha1(I) procollagen gene promoter by transfections with promoter-reporter constructs and reporter assays, and identify DNA binding proteins and confirm the functionality of the cis-elements by site directed mutagenesis; and third, we will identify alterations of the cis- and trans-acting elements involved in PGE2, IL- 1beta and TNFalpha inhibition of transcription of the alpha1(I) procollagen promoter in IPF fibroblasts. We expect that the application of advanced methods of molecular biology will allow the elucidation of the role that PG, IL-1beta, and TNFalpha may play in the pathogenesis of the severe fibrotic process occurring in the lung in patients with IPF.
| Diaz, A; Chepenik, K P; Korn, J H et al. (1998) Differential regulation of cyclooxygenases 1 and 2 by interleukin-1 beta, tumor necrosis factor-alpha, and transforming growth factor-beta 1 in human lung fibroblasts. Exp Cell Res 241:222-9 |
| Diaz, A; Jimenez, S A (1997) Interferon-gamma regulates collagen and fibronectin gene expression by transcriptional and post-transcriptional mechanisms. Int J Biochem Cell Biol 29:251-60 |
| Jimenez, S A; Diaz, A; Khalili, K (1995) Retroviruses and the pathogenesis of systemic sclerosis. Int Rev Immunol 12:159-75 |
