Phospholipase C (PLC) is a key enzyme in phosphoinositide signaling. We previously generated PLC-delta 1 knockout (KO) mice and found that these mice showed remarkable hair loss caused by abnormalities in hair follicle structures. Here we show that the skin of PLC-delta 1 KO mice displays typical inflammatory phenotypes, including increased dermal cellularity, leukocyte infiltration, and expression of pro-inflammatory cytokines. In addition, exogenously expressed PLC-delta 1 attenuates lipopolysaccharide-induced expression of IL-1 beta, a pro-inflammatory cytokine, in an enzymatic activity-dependent manner. Furthermore, suppression of skin inflammation by anti-inflammatory reagents cured the epidermal hyperplasia in PLC-delta 1 KO mice. Taken together, these results indicate that lack of PLC-delta 1 induces skin inflammation and that the epidermal hyperplasia in PLC-delta 1 KO mice is caused by skin inflammation. Our results also suggest that PLC-delta 1 regulates homeostasis of the immune system in skin. (c) 2007 Elsevier Inc. All rights reserved.