CD44 is a principal cell-surface receptor for hyaluronate and is found on a wide variety of cells. CD44 plays an important role in lymphocyte homing, lymphohemopoiesis, and T-cell activation as well as in cell motility and migration. CD44 is expressed on the cell surface of epidermal Langerhans cells (LC), and is one of the candidates for molecules that are involved in the migratory capability of LC, but little is known about its regulatory properties. We examined the modulatory effects of tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 on the CD44 expression in LC. We found 1) that TNF-alpha significantly up-regulated the expression of CD44 in a concentration-dependent manner, 2) that IL-10 down-regulated the expression of CD44 in a concentration-dependent manner, 3) that the effect of TNF-alpha or IL-10 was readily detectable as early as 24 h after the initiation of culture, and 4) that the simultaneous addition of TNF-alpha and IL-10 mutually neutralized the effect of each other. These data suggest that in the epidermal microenvironment the expression of CD44 in LC may be reciprocally regulated by TNF-alpha and IL-10, both of which are known to be produced by surrounding keratinocytes.