A new role for monocytes in modulating myometrial inflammation during human labor.

Here we fully characterize the cytokine profile of laboring human myometrium using Luminex analysis of 48 cytokine proteins, and stereologically quantified infiltration of monocytes and neutrophils into the myometrium. We hypothesized that monocytes can regulate their accumulation in the myometrium by disruption of proinflammatory cytokines to prevent an uncontrolled inflammatory response after labor onset. We isolated primary human myometrial cells (HMCs) from term, nonlaboring myometrial biopsies. Confluent HMCs were cocultured directly with human monocytic (THP-1) or lymphocytic (U937) cells, and with the same cells spatially separated by a membrane insert. After 72 h, HMCs and THP-1 were harvested separately, and RNA was extracted and analyzed by quantitative PCR. Coculture supernatants were collected and analyzed by Luminex assay and ELISA. We found that the laboring human myometrium produces significantly higher amounts of interleukin (IL) 6, IL9, IL18, IL1RA, CCL2, CCL7, CXCL8, CSF3, and tumor necrosis factor alpha, which coincides with the influx of immune cells. The direct contact or presence of THP-1 monocytes (but not U937 cells) significantly decreased CCL2 protein levels and increased IL1RA protein levels secreted by HMCs. This time-dependent decrease of CCL2 was greater with increasing number of monocytes being in direct contact with HMCs. We suggest a novel mechanism by which monocytes are first recruited to the myometrium by multiple cytokines and contribute to the physiologic inflammation of labor. After completing transmigration, activated monocytes disrupt locally established CCL2 gradients (possible by CCR2-mediated consumption) to limit their accumulation in the uterus. This mechanism may serve as a negative feedback loop to control the local inflammation and promote a return to homeostasis.

Physiologic uterine inflammation and labor onset: integration of endocrine and mechanical signals.

The mechanisms underlying the preparation of the uterus for labor are not fully understood. Our previous studies have shown that during pregnancy, the uterine muscle (myometrium) undergoes dramatic phenotypic modulation culminating in term labor. The current review will discuss the cellular mechanisms involved in the regulation of myometrial activity and its modulation by endocrine signals and by mechanical stimulation of the uterus by the growing fetus. In particular, the contribution of uterine inflammation to the onset of labor will be described. We provide evidence that increased production of cytokines/chemokines in pregnant myometrium is associated with uterine occupancy and regulated by progesterone, suggesting the integration of mechanical and endocrine signals. Myometrial cells can actively participate in the inflammatory process in the uterus through the release of multiple proinflammatory cytokines and chemokines, providing a strong signal for activation of immune cells, their subsequent infiltration into pregnant uterus, and the initiation of labor.