Intrauterine infection is still a common trigger of preterm delivery (PTD) and also a determinant risk factor for the subsequent development of neurodevelopmental abnormalities in neonates. In this study, we examined the expressional pattern of various inflammatory cytokines such as interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) in placentae complicated with severe chorioamnionitis (CAM) and found that IL-6 is mainly expressed in macrophages in villous mesenchyme by immunohistochemical analysis with anti-CD-68 antibody. Using an experimental lipopolysaccharide (LPS)-induced PTD model, the therapeutic potential of targeting this cytokine was investigated. Anti-IL-6 receptor antibody (MR16-1) was delivered 6 h before LPS treatment. Mice in the MR16-1 group had a significantly lower rate of PTD (17%) than in the controls (53%, P = 0.026). As a result, MR16-1 treatment significantly prolonged the gestational period (control; 18.4 ± 1.7d, MR16-1; 19.8 ± 1.5d, P = 0.007) without any apparent adverse events on the mice and their pups. In primary human amniotic epithelial cells, pretreatment with a humanized anti-human IL-6 receptor antibody, tocilizumab, significantly inhibited the production of prostaglandin E2 induced by IL-6. In conclusion, IL-6 was strongly expressed mainly in macrophages in villous mesenchyme in placentae complicated with CAM. Anti-IL-6R antibody significantly decreased the rate of PTD in LPS-induced inflammatory model in mice, and inhibited PGE2 production from human primary amniotic epithelial cells. Targeting IL-6 signaling could be a promising option for the prevention of PTD and needs to be further explored for future clinical application.
Akirin2, an evolutionarily conserved nuclear protein, is an important factor regulating inflammatory gene transcription in mammalian innate immune cells by bridging the NF-κB and SWI/SNF complexes. Although Akirin is critical for Drosophila immune responses, which totally rely on innate immunity, the mammalian NF-κB system is critical not only for the innate but also for the acquired immune system. Therefore, we investigated the role of mouse Akirin2 in acquired immune cells by ablating Akirin2 function in B lymphocytes. B cell–specific Akirin2-deficient (Cd19Cre/+Akirin2fl/fl) mice showed profound decrease in the splenic follicular (FO) and peritoneal B-1, but not splenic marginal zone (MZ), B cell numbers. However, both Akirin2-deficient FO and MZ B cells showed severe proliferation defect and are prone to undergo apoptosis in response to TLR ligands, CD40, and BCR stimulation. Furthermore, B cell cycling was defective in the absence of Akirin2 owing to impaired expression of genes encoding cyclin D and c-Myc. Additionally, Brg1 recruitment to the Myc and Ccnd2 promoter was severely impaired in Akirin2-deficient B cells. Cd19Cre/+Akirin2fl/fl mice showed impaired in vivo immune responses to T-dependent and -independent Ags. Collectively, these results demonstrate that Akirin2 is critical for the mitogen-induced B cell cycle progression and humoral immune responses by controlling the SWI/SNF complex, further emphasizing the significant function of Akirin2 not only in the innate, but also in adaptive immune cells.
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