Consequences of Stat6 deletion on Sis/PDGF- and IL-4-induced proliferation and transcriptional activation in murine fibroblasts.
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.
Kriebel
P
P
Laboratory of Cellular and Molecular Biology, National Cancer Institute, Building 37 Room 1E24, Bethesda, Maryland, MD 20892, USA.
Patel
B K
BK
Nelson
S A
SA
Grusby
M J
MJ
LaRochelle
W J
WJ
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*
D010982:Platelet-Derived Growth Factor; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4