G2A is a stress-inducible G protein-coupled receptor for oxidized free fatty acids, such as 9-hydroxyoctadecadienoic acid (HODE). As skin is routinely and pathologically exposed to many oxidative stresses such as UV radiation, chemical agents, and inflammation that might induce both G2A expression and production of G2A ligands, we examined G2A function in human keratinocytes. G2A was expressed in human epidermis, normal human epidermal keratinocytes (NHEK), and an immortalized human keratinocyte cell line (HaCaT). 9(S)-HODE evoked intracellular calcium mobilization and secretion of cytokines, including IL-6, IL-8, and GM-CSF in NHEK cells. These responses became prominent in HaCaT cells by overexpression of G2A. 9(S)-HODE inhibited proliferation of NHEK cells by suppressing DNA synthesis and arresting the cell cycle in the G0/1-phase. On the other hand, 13(S)-HODE, another major oxidative product from linoleate, showed little or no effect on either cytokine secretion or on proliferation in NHEK cells. A small interfering RNA designed to downregulate G2A caused suppression of 9(S)-HODE-induced inhibitory effects on proliferation of NHEK cells. UVB and H(2)O(2) induced G2A expression and caused oxidation of linoleate to produce 9-HODE in HaCaT cells. These results suggest that 9-HODE-G2A signaling plays proinflammatory roles in skin under oxidative conditions.