Relaxin augments the inflammatory IL6 response in the choriodecidua

Abstract

Intrauterine infection frequently leads to preterm birth (PTB), with the pathophysiology involving activation of the innate immune system and its associated inflammatory response. The choriodecidua produces relaxin (RLN) and elevated levels are associated with preterm premature rupture of the fetal membranes. However, it is not increased in bacterially-mediated PTB, but may act as an endogenous sterile inflammatory mediator. Elevated systemic RLN levels from the corpus luteum are also associated with PTB, but the mechanism is unknown. In clinical obstetrics, intrauterine inflammation or infection can coexist with elevated RLN. Therefore, in this study, we further characterized the effects of RLN alone or together with an inflammatory mediator on the production of IL1B, CSF2 (GM-CSF), IL6, IL8 and TNF, from chorionic cytotrophoblasts (CyT), decidual fibroblasts (DF) and stromal cells (DSC), using interleukin-1 beta (IL1B) to mimic sterile inflammation or lipopolysaccharide (LPS) for bacterial infection. Endogenous differences between the cells showed that the CyT expressed more and the RXFP1, its receptor RXFP1 splice variant D. CyT also showed the most robust cAMP response to RLN with increased IL6 secreted after 4 h, preceded by increased transcription at 1 h, likely due to activation of RXFP1 and cAMP. When all cell types were treated with IL1B and RLN, RLN augmented secretion of IL6 and IL8 from CyT and DF, but not DSC. Similarly, RLN augmented LPS-induced IL6 secretion from CyT and DF. Despite the structural similarity between TLR4 and RXFP1, blocking TLR4 in CyT had no effect on RLN-induced IL6 secretion, suggesting specific activation of RXFP1. Thus, we have shown that in the presence of a low level of intrauterine inflammation/infection, elevated RLN could act on the CyT and DF to augment the inflammatory response, contributing to the pathophysiology of PTB.

Evidence for a Role for the Adaptive Immune Response in Human Term Parturition

“…Our data and that of others, who have reported that decidual neutrophils in term pregnancies provide a rich source of extracellular matrix proteases 4,16,[178][179][180] and cytokines, 12,33,74,80,92,181 suggest that granulocytes may play a role before and during spontaneous labor at term (before labor for the preparative stages for parturition). As the depletion of neutrophils in the mouse does not affect the timing or course of labor 132 and that other leukocytes and stromal cells produce these and other related immunological media-tors, 83,[182][183][184][185][186][187][188] it would seem that granulocytes are not an absolutely required for labor in mice. We favor a model in which there is cooperation of the different cell types to achieve normal parturition at term.…”

“…Previous studies conducted by our group and others have demonstrated the importance of the choriodecidual microenvironment in spontaneous parturition in humans, strengthening the role of the innate immune system in labor. 17,19,21,22,80–83 …”

“…Previous studies conducted by our group and others have demonstrated the importance of the choriodecidual microenvironment in spontaneous parturition in humans, strengthening the role of the innate immune system in labor. 17,19,21,22,[80][81][82][83] Leukocyte recruitment appears to be the first step in the conditioning of this microenvironment as term approaches. We have proposed that activated leukocytes extravasate from the local circulation into the choriodecidua in preparation for labor.…”

Genetic associations of relaxin: preterm birth and premature rupture of fetal membranes

“…12,13 It can also directly modulate the production of the proinflammatory cytokines, IL-6 and IL-8 produced by both the chorion and decidua. 14,15 However, there has been no attempt to date, to integrate the data on the systemic and intrauterine RLN in either normal gestation or in sPTB.…”

Serum relaxin and cervical length for prediction of spontaneous preterm birth in second‐trimester symptomatic women

“…In pregnancy, relaxin is produced by the placenta, membranes and decidua, and exerts both local and systemic effects. Experimental data show that relaxin can augment the intrauterine inflammatory response, affect myometrial contractility through cyclooxygenase‐1 (COX‐1) and COX‐2 activation, and upregulate MMPs. Even so, serum levels of relaxin are not necessarily expected to reflect accurately the local concentration and effects of the hormone at the choriodecidual level.…”