Extracellular ATP and P2 receptors are reported to be involved in interleukin-6 (IL-6) production by human keratinocytes, but the role of extracellular ATP in cytokine-induced IL-6 production remains unclear. In this study, we investigated the involvement of various P2 receptors in IL-6 production induced by the Th1 cytokine interferon-gamma (IFN-γ) in a human keratinocyte cell line, HaCaT. IFN-γ increased IL-6 production in HaCaT cells. A non-selective antagonist of P2Y receptors (suramin), a selective P2Y11 receptor antagonist (NF157), ecto-nucleotidase (apyrase), and a soluble adenylate cyclase inhibitor (KH7) all inhibited IL-6 production. It was further confirmed that ATP was released from HaCaT cells stimulated with IFN-γ. These results suggest that extracellular ATP and P2Y11 receptor are involved in IFN-γ-induced IL-6 production. Knockdown of P2Y11 receptor suppressed IL-6 production, strongly supporting this idea. In conclusion, these data demonstrate that P2Y11 receptor mediates IFN-γ-induced IL-6 production in human keratinocytes, and suggest the importance of purinergic signaling in IFN-γ-induced skin inflammatory conditions, such as psoriasis.