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IL-6 and Tgf-β have been shown to play a role in skin development and maintenance. However, a link between these two cytokines has yet to be identified therefore; therefore, in this study we investigated the modulation of Tgf-β1 and Tgf-βR2 by IL-6 in skin. Recombinant IL-6 treatment of IL-6KO lattices and intradermal injections of IL-6 into unwounded mice showed a significant induction of Tgf-β1 mRNA and protein, where Tgf-β1 expression localized in the dermis, while Tgf-βR2 expression resided primarily in the epidermis in IL-6KO mice. IL-6 also increased Tgf-βR2 mRNA and protein expression, and potentiates TGFb mediated decreases in proliferation in cultured keratinocytes. Wounded IL-6KO and C57BL/6 control mice showed Tgf-β1 and βR2 mRNA expression was significantly greater in unwounded and seven day-old wounds from WT mice, however; protein expression was not different. Use of inhibitors indicated that IL-6 modulates Tgf-β through a Mapk/Erk dependent mechanism. These studies indicate that IL-6 has the ability to modulate the expression of Tgf-β and Tgf-βR2 mRNA in dermal fibroblasts and unwounded skin through a Mapk/Erk dependent mechanism. Protein expression levels indicated additional regulation by factors other than IL-6 within the wound. IL-6 treatment also potentiates the differentiative effects of Tgf-β on cultured keratinocytes. These results may provide a possible mechanism defining the role of IL-6 in skin maintenance and may indicate a new association of IL-6 with Tgf-β in pathologies associated fibrosis. This work was funded by NIH/NIGMS grant R01 GM067745.