The Dual Role of IL-22: Balancing Protection and Risk in Pregnancy during Inflammatory Challenges.

Objective: To investigate the potential of recombinant IL-22 (rIL-22) in preventing inflammation-triggered abortion.

Design: Using wild type (WT, C57BL/6J) and IL-22 knock out (IL-22^-/-) mice aged 7-14 weeks, we induced abortion via intraperitoneal injection of lipopolysaccharide (LPS) on gestational day (GD) 8.5, mimicking inflammatory challenges encountered during mid-gestational pregnancy. Prior to LPS administration, mice were treated with varying doses of rIL-22 via tail vein injection. Uterine tissue was harvested 48 hours post-LPS injection (n=6/group), or mice were monitored until delivery (GD 20.5) (n=3/group). Transepithelial electric resistance assessed transport integrity of tight junction in uterine epithelial cell culture. Gene expression levels were quantified using qRT-PCR, while immunohistochemistry/immunofluorescence evaluated tissue distribution of relevant antigens. Multiplex-based immunoassay analysis was used to measure immune markers in the amniotic fluid.

Results: Administration of rIL-22 to IL-22^-/- mice not only restored the endometrial mucosal architecture to levels similar to those of WT animals but also prevented abortion in a dose-dependent manner. While rIL-22 treatment rescued pregnancy in IL-22^-/- mice at doses of 5, 10, and 20 μg/mouse, only the lower doses (≤10 μg/mouse) were effective in WT mice. High dose (20 μg/mouse) of rIL-22, when followed by LPS injection, negatively affected pregnancy outcomes in WT mice, and the sole administration of 20 μg of rIL-22 resulted in adverse pregnancy outcomes in both genotypes.

Conclusions: IL-22 emerges as a promising therapeutic target in reproductive medicine, offering potential avenues for preserving pregnancy in the face of inflammatory challenges. However, increased levels of IL-22 could be associated with reproductive failures, emphasizing the delicate balance required for immune regulation. Our study underscores the importance of immune regulation in reproductive health and highlights rIL-22 as a novel candidate for improving pregnancy outcomes in inflammatory conditions.