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Consequences of Stat6 deletion on Sis/PDGF- and IL-4-induced proliferation and transcriptional activation in murine fibroblasts

Oncogene volume 18, pages 7294–7302 (1999)Cite this article

Abstract

Aberrant communication among growth factors and cytokines that regulate tissue homeostasis often results in malignancy. Among the many cell types that participate in this process, stromal fibroblasts communicate in a paracrine and juxtracrine manner with cells of epithelial, endothelial, and hematopoietic origin. For fibroblasts, platelet-derived growth factor (PDGF) is a major proliferative and differentiation agent. Interleukin-4 (IL-4), however, possesses only modulating functions in this cell type. Here, we investigated the consequences of deleting Stat6 on PDGF and IL-4 signaling, proliferation, and transcriptional activation by establishing and characterizing early passage fibroblasts from wild-type and Stat6 null mice. Both wild-type and Stat6−/− fibroblasts showed nearly identical PDGFR and IL-4R activation, gross substrate tyrosine phosphorylation, PI 3-kinase activation, as well as Stat1, 3 and 5 DNA binding activities. Unexpectedly, IL-4's enhancement of PDGF-induced [3H]thymidine incorporation was greatly diminished in Stat6−/−, but not wild-type fibroblasts. PDGF-induced [3H]thymidine uptake was largely unaffected. Strikingly, IL-4, but not PDGF induction of the proinflammatory gene products, IL-6 and MCP-1 was markedly reduced in Stat6−/− fibroblasts. Thus, Stat6 is an important and specific mediator of IL-4-enhanced PDGF-induced proliferation as well as IL-4's transcriptional activation of IL-6 and MCP-1.

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Acknowledgements

We thank Drs Jackie Pierce, Stuart Rudikoff, Matt Lorenzi, Marcio Chedid, and Ling-Mei Wang for helpful discussions. We also acknowledge Nelson Ellmore and Veena Kapoor for valuable technical assistance. We thank Dr Stuart Rudikoff for providing the murine IL-6 cDNA probe and Dr Keith Peden for his generous gift of the SV40 large T antigen. MJ Grusby is a Scholar of the Leukemia Society of America and supported by NIH grant AI40171, as well as a gift from the Mathers Foundation.

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  1. Laboratory of Cellular and Molecular Biology, National Cancer Institute, Building 37 Room 1E24, Bethesda, 20892, Maryland, MD, USA

    Paul Kriebel, Bharvin KR Patel, Stefanie A Nelson & William J LaRochelle

  2. Department of Cancer Biology, Harvard School of Public Health, Harvard Medical School, Boston, 02115, Massachusetts, MA, USA

    Michael J Grusby

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Kriebel, P., Patel, B., Nelson, S. et al. Consequences of Stat6 deletion on Sis/PDGF- and IL-4-induced proliferation and transcriptional activation in murine fibroblasts. Oncogene 18, 7294–7302 (1999). https://doi.org/10.1038/sj.onc.1203148

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