Recent studies have suggested a significant increase in corticotropin releasing hormone (CRH) in maternal plasma and placenta during the course of maternal infection. The aim of this study was to examine the possible role of CRH in lipopolysaccharide (LPS)-induced pro-inflammatory cytokine expression using the well-established human extravillous trophoblast cell line HTR-8/SVneo. Exposure of the HTR-8/SVneo cells to LPS resulted in increased secretion of tumour necrosis factor alpha (TNF-alpha) and interleukin (IL)-8. Pre-treatment of the cells with CRH prior to LPS exposure significantly enhanced LPS induced TNF-alpha and IL-8 secretion. This effect was inhibited by the CRH antagonist astressin. Stimulation of the cells with CRH caused a rapid and transient phosphorylation of p38/MAPK while CRH had no effect on ERK1/2 activation. The effect of CRH on p38/MAPK activation was suppressed by astressin and by the p38/MAPK inhibitor SB203580. Exposure of the cells to CRH resulted in increased expression of TLR-4 and this effect was also inhibited by astressin. Taken together, these findings suggest that CRH augments LPS induced cytokine secretion in human trophoblast cells. Modulation of LPS induced immune responses by CRH may be mediated through regulation of TLR-4 and selective activation of the p38/MAPK signalling pathway.