Corticotrophin releasing hormone (CRH) is recognized as the hypothalamic neuropeptide that regulates the hypothalamus-pituitary-adrenal (HPA) axis in mammals, orchestrating neuroendocrine, autonomic, and immunologic responses to stress. During pregnancy placenta represents the main source of CRH, acting via autocrine, paracrine and endocrine mechanisms, plays a critical role in the maintenance of pregnancy and regulates neuroendocrine and inflammatory events leading to physiological parturition and its premature onset (1). Neuroendocrine and immune systems interact at various levels. Interestingly, CRH serves a pro-inflammatory function by activating the immune/inflammatory response in several conditions (2). Indeed at the maternal-fetal interface, trophoblast cells produce pro-inflammatory cytokines in response to physiological and pathological conditions (4) and recent evidences have shown that CRH enhances LPS-induced pro-inflammatory cytokine expression, such as TNF-α and IL-8, in human trophoblast cells, through activation of p38/MAPK signalling and TLR-4 expression (3). CRH exerts its biological effects by binding two G protein-coupled receptors named CRHR1 and CRHR2, both expressed by utero-placental tissues, with a prevalent affinity for CRHR1. Since antalarmin, the CRHR1 antagonist, has shown to suppress CRH effects on peripheral inflammation in non-gestational tissues, it is believed that CRHR1 may represent the main receptor mediating the pro-inflammatory effects of CRH (4). Recently, an increasing interest has been developed for the urocortins (Ucn, Ucn2, Ucn3) that belong to the CRH family neuropeptides and exert complementary or sometimes contrasting actions to fine-tune CRH biological effects. Urocortins bind the CRH receptors with different affinity, in fact Ucn has approximately the same affinity for both receptors, whereas Ucn2 and Ucn3 bind only CRHR2 (1). Ucn is expressed by intrauterine tissues (human placenta, decidua, and fetal membranes) throughout pregnancy and maternal plasma concentrations remain constant until term and increase significantly during term and preterm labour. Moreover, since Ucn levels in fetal circulation are higher than in maternal plasma, while Ucn mRNA expression doesn’t change between labouring and non-labouring placenta, a fetal source of the peptide has been hypothesized at term and preterm parturition (1). Similarly to CRH, Ucn acts as an endogenous immunomodulatory factor, but showing predominant anti-inflammatory effects and immune tolerance maintenance (2). Indeed, our group has recently demonstrated that Ucn modulates LPS-induced secretion of the pro-inflammatory TNF-α and increases the basal secretion of anti-inflammatory cytokines (IL-4, IL-10) from trophoblast cultures through CRH-R2, suggesting that Ucn may modulate the placental inflammatory responses leading to physiological and pathological parturition (4). Ucn2 and Ucn3 are expressed in early and late gestational tissues (human placenta, decidua, and fetal membranes) and mRNA levels are increased at lower oxygen tensions, but their role in the mechanism of term and preterm delivery remains unknown (6). With respect to their involvement on inflammatory pathways, some studies suggest that Ucn2 exerts mainly pro-inflammatory activity while Ucn3 may regulate anti-inflammatory effects in non-gestational tissues, although binding the same receptor (6). Indeed, recent in vitro data obtained by our group have shown that Ucn2 increases the pro-inflammatory while Ucn3 the anti-inflammatory cytokines secretion via CRHR2 in trophoblast cultures (unpublished work). Finally, we have recently found that intrauterine inflammatory/infective pathways such as chorioamnionitis associated with preterm delivery activate placental CRH/Ucns pathways in vivo (7). In fact, trophoblast samples collected from preterm deliveries associated with chorioamnionitis have shown up-regulation of CRH, Ucn2 and CRHR1 genes and down-regulation of Ucn, Ucn3 and CRHR2 genes in comparison to preterm deliveries not associated with chorioamnionitis. Furthermore, these changes have been reproduced in vitro by treating placental trophoblast with LPS, suggesting their potential importance in infection-mediated preterm labour. In conclusion, CRH peptides and receptors modulate inflammatory responses in utero-placental tissues and their placental expression is activated when inflammatory/infective processes occur, suggesting their role as important mediators of the interactions between neuroendocrine and immune systems leading to parturition and its premature onset.