Editorial: The Oxytocin/Oxytocin Receptor System—Expect the Unexpected

In this issue of Endocrinology, Schmid et al. (1) demonstrate that both IL-1β and IL-6 play a negative role in the transcriptional regulation of the human oxytocin receptor (OTR) gene in human immortalized myometrial cells in culture. Interestingly, these results are opposite to the initial hypothesis of the authors, who expected both IL-1β and IL-6 to induce OTR gene expression, consistently with the promoting role of proinflammatory cytokines in mediating preterm and term labor (2, 3) and with the presence of several putative binding sites for nuclear factor-IL6 (NF-IL6) in the 5′-flanking region of the OTR gene (1). These observations are in line with several studies in recent years indicating that the distribution, biological significance, and regulation of the OT/OTR system are unexpectedly much more complex and varied than previously postulated (4). For a long time, OT and OTR traditionally have been considered mainly involved in the regulation of reproductive functions such as the timing and amplification of labor, ovulation, and lactation among others. Subsequently, it became evident that they also participate in the regulation of different behavioral, neuro-mediated functions, including sexual and maternal behavior, memory, food and drink intake, and modulation of anorexia (5). According to these different roles in reproduction and behavior, OTRs were initially identified in the functionally related tissues (uterus, feto-maternal unit, breast, and central nervous system). Similarly, studies on the pathophysiology of the OT/OTR system, including regulation of OTR expression and intracellular signaling, were first focused on these sites. However, recently the biological implications of the OT/OTR interplay have been widely extended because different target tissues hosting OTR, new factors involved in OTR modulation, and possible alternative signaling pathways have been identified. The availability of the highly selective radioiodinatable ligand 125[I]d(CH2)5[Tyr(Me)2, Thr4, Tyr-NH29]OVT[ 125I-OTA] (6) has led to the discovery of OTR in tissues other than those known to be target of OT action. Among these, two are especially striking: endothelial cells (7, 8) and osteoblasts (9).