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

Aberrant communication among growth factors and cytokines that regulate tis sue homeostasis often results in malignancy. Among the many cell types that participate in this process, stromal fibroblasts communicate in a paracrin e and juxtracrine manner with cells of epithelial, endothelial, and hematop oietic origin. For fibroblasts, platelet-derived growth factor (PDGF) is a major proliferative and differentiation agent, Interleukin-4 (IL-4), howeve r, possesses only modulating functions in this cell type. Here, we investig ated the consequences of deleting Stat6 on PDGF and IL-4 signaling, prolife ration, and transcriptional activation by establishing and characterizing e arly passage fibroblasts from wild-type and Stat6 null mice. Both wild-type and Stat6(-/-) fibroblasts showed nearly identical PDGFR and IL-4R activat ion, gross substrate tyrosine phosphorylation, PI 3-kinase activation, as w ell as Stat1, 3 and 5 DNA binding activities. Unexpectedly, IL-4's enhancem ent of PDGF-induced [H-3]thymidine incorporation was greatly diminished in Stat6(-/-), but not wild-type fibroblasts, PDGF-induced [H-3]thymidine upta ke was largely unaffected. Strikingly, IL-3, 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- 1-enhanced PDGF-induced proliferation as well as IL-4's transcriptional act ivation of IL-6 and MCP-1.