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Disease conditions associated with pulmonary fibrosis are progressive and have a poor long-term prognosis with irreversible changes in airway architecture leading to marked morbidity and mortalities. Using murine models we demonstrate a role for interleukin (IL)-25 in the generation of pulmonary fibrosis. Mechanistically, we identify IL-13 release from type 2 innate lymphoid cells (ILC2) as sufficient to drive collagen deposition in the lungs of challenged mice and suggest this as a potential mechanism through which IL-25 is acting. Additionally, we demonstrate that in human idiopathic pulmonary fibrosis there is increased pulmonary expression of IL-25 and also observe a population ILC2 in the lungs of idiopathic pulmonary fibrosis patients. Collectively, we present an innate mechanism for the generation of pulmonary fibrosis, via IL-25 and ILC2, that occurs independently of T-cell-mediated antigen-specific immune responses. These results suggest the potential of therapeutically targeting IL-25 and ILC2 for the treatment of human fibrotic diseases. [ABSTRACT FROM AUTHOR]

Increased numbers of S100A4+ cells are associated with poor prog- nosis in patients who have cancer. Although the metastatic capabil- ities of S100A4+ cancer cells have been examined, the functional role of S100A4+ stromal cells in metastasis is largely unknown. To study the contribution of S100A4+ stromal cells in metastasis, we used transgenic mice that express viral thymidine kinase under control of the S100A4 promoter to specifically ablate S100A4+ stromal cells. Depletion of S100A4+ stromal cells significantly reduced metastatic colonization without affecting primary tumor growth. Multiple bone marrow transplantation studies demonstrated that these effects of S100A4+ stromal cells are attributable to local non-bone marrow-derived S100A4+ cells, which are likely fibroblasts in this setting. Reduction in metastasis due to the loss of S100A4+ fibro-blasts correlated with a concomitant decrease in the expression of several ECM molecules and growth factors, particularly Tenascin-C and VEGF-A. The functional importance of stromal Tenascin-C and S100A4+ fibroblast-derived VEGF-A in metastasis was established by examining Tenascin-C null mice and transgenic mice expressing Cre recombinase under control of the S100A4 promoter crossed with mice carrying VEGF-A alleles flanked by loxP sites, which exhibited a significant decrease in metastatic colonization without effects on primary tumor growth. In particular, 5100A4 fibroblast-derived VEGF-A plays an important role in the establishment of an angiogenic microenvironment at the metastatic site to facilitate coloniza- tion, whereas stromal Tenascin-C may provide protection from apoptosis. Our study demonstrates a crucial role for local S100A4+ fibroblasts in providing the permissive "soil" for metastatic coloni- zation, a challenging step in the metastatic cascade. [ABSTRACT FROM AUTHOR]

Examines the gene expressions of human and mouse transcriptomes. Transcriptional activity of biological samples; Mechanism of transcriptional regulation; Sequence of mammalian genome.