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Review
. 2012:2012:270670.
doi: 10.1155/2012/270670. Epub 2012 Jul 31.

Possible roles of proinflammatory and chemoattractive cytokines produced by human fetal membrane cells in the pathology of adverse pregnancy outcomes associated with influenza virus infection

Noboru Uchide  1 , Kunio Ohyama, Toshio Bessho, Makoto Takeichi, Hiroo Toyoda
Affiliations
Review

Possible roles of proinflammatory and chemoattractive cytokines produced by human fetal membrane cells in the pathology of adverse pregnancy outcomes associated with influenza virus infection

Noboru Uchide et al. Mediators Inflamm. 2012.

Abstract

Pregnant women are at an increased risk of influenza-associated adverse outcomes, such as premature delivery, based on data from the latest pandemic with a novel influenza A (H1N1) virus in 2009-2010. It has been suggested that the transplacental transmission of influenza viruses is rarely detected in humans. A series of our study has demonstrated that influenza virus infection induced apoptosis in primary cultured human fetal membrane chorion cells, from which a factor with monocyte differentiation-inducing (MDI) activity was secreted. Proinflammatory cytokines, such as interleukin (IL)-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-β, were identified as a member of the MDI factor. Influenza virus infection induced the mRNA expression of not only the proinflammatory cytokines but also chemoattractive cytokines, such as monocyte chemoattractant protein (MCP)-1, regulated on activation, normal T-cell expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-1β, IL-8, growth-regulated oncogene (GRO)-α, GRO-β, epithelial cell-derived neutrophil-activating protein (ENA)-78, and interferon inducible protein (IP)-10 in cultured chorion cells. These cytokines are postulated to associate with human parturition. This paper, therefore, reviews (1) lessons from pandemic H1N1 2009 in pregnancy, (2) production of proinflammatory and chemoattractive cytokines by human fetal membranes and their functions in gestational tissues, and (3) possible roles of cytokines produced by human fetal membranes in the pathology of adverse pregnancy outcomes associated with influenza virus infection.

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Figures

Figure 1
Figure 1
List of anti-influenza drugs currently available.
Figure 2
Figure 2
Diagrammatic representation of the human fetal membranes. The amnion and chorion are attached together by the sponge layer. The amnion is formed of a single-layered amniotic epithelial cell and compact and fibroblast layers. The chorion is formed of multilayered trophoblast cells and reticular layer. The fibroblast layer of the amnion and the reticular layer of the chorion contain mesenchymal cells. The mesenchymal cells exhibit plasticity among fibroblast/myofibroblast cells and macrophages.
Figure 3
Figure 3
Pharmacological agents with inhibitory effect on the production of proinflammatory cytokines by human fetal membrane cells.
Figure 4
Figure 4
Pharmacological agents with inhibitory effect on the induction of apoptosis in human fetal membrane cells. Abbreviations used: NDGA, nordihydroguaiaretic acid; PDTC, pyrrolidine dithiocarbamate.
Figure 5
Figure 5
Differential mRNA expression of chemoattractive cytokines and MDI factor among cultured chorion, amnion mesenchymal, and amnion epithelial cells in response to influenza virus infection. In cultured chorion cells, the levels of mRNA expression of all of 7 chemokines tested (i.e., ENA-78, MCP-1, GRO-α/β, IP-10, RANTES, MIP-1β, and IL-8) were increased by influenza virus infection. In cultured amnion mesenchymal cells, the levels of mRNA expression of 6 chemokines except for ENA-78 (i.e., MCP-1, GRO-α/β, IP-10, RNATES, MIP-1β, and IL-8) were increased. In cultured amnion epithelial cells, the levels of mRNA expression of 3 chemokines (RANTES, MIP-1β, and IL-8) were increased. Influenza virus infection induced the expression of IL-1β and IL-6 mRNAs in chorion and amnion mesenchymal cells but not in amnion epithelial cells. The expression of TNF-α and IFN-β mRNAs was induced in three types of cells by influenza virus infection. Abbreviations used: ENA-78, epithelial cell-derived neutrophil-activating protein 78; GRO-α/β, growth-related oncogene α/β; IL, interleukin; IP-10, interferon inducible protein 10; MCP-1, monocyte chemoattractant protein 1; MDI, monocyte differentiation-inducing; MIP-1β, macrophage inflammatory protein 1β; RANTES, regulated on activation, normal T cell expressed and secreted.
Figure 6
Figure 6
Multistage roles of chemoattractive cytokines and MDI factor produced by chorion, amnion mesenchymal, and amnion epithelial cells in the recruitment and differentiation of phagocytes. When influenza viruses spread from mother to the chorion cell layer at the first stratum, ENA-78, GRO-α/β, and IL-8 may be firstly produced to recruit a first unit of neutrophils by only chorion cells that are located on the maternal-fetal interface. The chorion cells may produce MCP-1, IP-10, RANTES, and MIP-1β to recruit maternal circulating monocyte, IL-6, TNF-α, and IFN-β to differentiate the recruited maternal monocytes, and the staying fetal amnion mesenchymal cells to macrophages. When the viruses got over the chorion cell layer and spread to the amnion mesenchymal cell layer at the second stratum, the amnion mesenchymal cells may produce GRO-α/β and IL-8 to recruit a second unit of neutrophils as reinforcements, MCP-1, IP-10, RANTES, and MIP-1β to recruit maternal circulating monocytes, and IL-6, TNF-α and IFN-β to differentiate the recruited maternal monocytes and the staying fetal amnion mesenchymal cells to macrophages as well as the chorion cells. If the virus spread to the amnion epithelium as a final cellular barrier, the amnion epithelial cells may produce IL-8 to recruit a third unit of neutrophils and RANTES and MIP-1β to recruit fetus-derived macrophages differentiated from the staying amnion mesenchymal cells. Abbreviations used: ENA-78, epithelial cell-derived neutrophil-activating protein 78; GRO-α/β, growth-related oncogene α/β; IL, interleukin; IP-10, interferon inducible protein 10; MCP-1, monocyte chemoattractant protein 1; MDI, monocyte differentiation-inducing; MIP-1β, macrophage inflammatory protein 1β; RANTES, regulated on activation, normal T cell expressed and secreted.
Figure 7
Figure 7
Hypothetical tissue injury model with special emphases of the interaction between human fetal membrane chorion cells and two types of phagocytes. Influenza virus infection induces apoptosis and the gene expression of the MDI factor (i.e., IL-6, TNF-α and IFN-β), monocyte-attractive chemokines (MCP-1, RANTES, MIP-1β and IP-10) and neutrophil-attractive chemokines (IL-8, GRO-α/β and ENA-78) in human fetal membrane chorion cells. The monocyte- and neutrophil-attractive chemokines recruit maternal monocytes and neutrophils circulating in the bloodstream into the infected region, respectively. The MDI factor (i.e., IL-6, TNF-α and IFN-β) differentiates the recruited maternal monocytes and the staying fetal amnion mesenchymal cells to mature macrophages. The mature macrophages and neutrophils phagocytose the apoptotic cell debris of chorion cells resulting from apoptosis. Subsequent to phagocytosis, an abrupt increase in superoxide production by macrophages and neutrophils, known as the oxidative burst, occurs, which is catalyzed by NADPH oxidase enzyme complex. Superoxide produced by phagocytes engulfing chorion cells undergoing apoptosis may injure tissues through inducing apoptosis in noninfected cells in vivo situation, resulting in the formation of necrotic foci. Abbreviations used: ENA-78, epithelial cell-derived neutrophil-activating protein 78; GRO-α/β, growth-related oncogene α/β; IL, interleukin; IP-10, interferon inducible protein 10; MCP-1, monocyte chemoattractant protein 1; MDI, monocyte differentiation-inducing; MIP-1β, macrophage inflammatory protein 1β; NADPH, nicotinamide adenine dinucleotide phosphate; RANTES, regulated on activation, normal T cell expressed and secreted.
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