Immune activation of fibrosis likely plays a crucial role in the pathogenesis of systemic sclerosis (SSc). The goal of this study was to better understand innate immune regulation and associated IFN- and TGFβ-responsive gene expression in SSc skin and dermal fibroblasts, in particular the effect of different Toll-like receptor (TLR) ligands. To better understand the relationship between inflammation and fibrosis in vivo we developed a murine model for chronic innate immune stimulation. We found that expression of both IFN- and TGFβ-responsive genes are increased in SSc skin and in SSc fibroblasts when stimulated by TLR ligands. In contrast, cutaneous lupus skin showed much more highly upregulated IFN-responsive and much less highly upregulated TGFβ-responsive gene expression. The TLR3 ligand, Poly(I:C), mostly highly increased fibroblast expression of both IFN- and TGFβ-responsive genes as well as TLR3. Chronic subcutaneous immune stimulation by Poly(I:C) stimulated inflammation, and IFN- and TGFβ-responsive gene expression. However, in this model type I IFNs played no apparent role regulating TGFβ activity in the skin. These results suggest that TLR agonists may be important stimuli of dermal fibrosis, potentially mediated by TLR3 or other innate immune receptors.