Withangulatin A (WA), a bioactive withanolide isolated from Physalis angulata L, has a strong immunosuppressive activity. We have demonstrated that WA significantly suppressed the over-proliferation of ConA-induced T lymphocytes in a dose- and time-dependent manner, which modulated Th1/Th2-type balance dramatically. Moreover, WA-induced heme oxygenase 1 (HO-1) expression in mice T lymphocytes through the ERK/MAPK pathway and inhibited ConA-induced nuclear factor kappa B (NF-kappa B p65) nuclear translocation, directly or indirectly mediated by HO-1. Notably, WA affected the expression of COX-2 and PPAR-gamma in ConA-induced T lymphocytes. The synergistic manner in which WA enhanced HO-1 expression through the ERK/MAPK pathway and NF-kappa B nuclear translocation and other regulatory proteins, thereby restricting T lymphocytes from over-expression and modulating Th1/Th2-type balance, could be the mechanism for the immunosuppressive properties of WA, the immunosuppressive effect of which may protect against autoimmune disorder diseases. (C) 2010 Elsevier Ltd. All rights reserved.