title: Consequences of Stat6 deletion on Sis/PDGF- and IL-4-induced proliferation and transcriptional activation in murine fibroblasts.
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.
authors.affiliation: Laboratory of Cellular and Molecular Biology, National Cancer Institute, Building 37 Room 1E24, Bethesda, Maryland, MD 20892, USA.
authors.forename: P
authors.initials: P
authors.lastname: Kriebel
authors.forename: B K
authors.initials: BK
authors.lastname: Patel
authors.forename: S A
authors.initials: SA
authors.lastname: Nelson
authors.forename: M J
authors.initials: MJ
authors.lastname: Grusby
authors.forename: W J
authors.initials: WJ
authors.lastname: LaRochelle
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002461:Cell Line, Transformed; D005347:Fibroblasts / Q000473:pathology* / Q000502:physiology*; D017353:Gene Deletion; D015847:Interleukin-4 / Q000494:pharmacology*; D051379:Mice; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics*
chemical_list: D010982:Platelet-Derived Growth Factor; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4