Interferon gamma (IFN-c) and leukemia inhibitory factor (LIF) are key gestational factors that may differentially affect leukocyte function during gestation. Because IFN-c induces a pro-inflammatory phenotype in macrophages and because trophoblast cells are principal targets of LIF in the placenta, we investigated whether and how soluble factors from trophoblast cells regulate the effects of IFN-c on macrophage activation. IFN-c reduces macrophage motility, but enhances Stat1 activation, pro-inflammatory gene expression and cytotoxic functions. Soluble factors from villous cytotrophoblasts (vCT1LIF cells) and BeWo cells (BW/ST1LIF cells) that were differentiated in the presence of LIF inhibit macrophage Stat1 activation but inversely sustain Stat3 activation in response to IFN-c. vCT1LIF cells produce soluble factors that induce Stat3 activation; this effect is partially abrogated in the presence of neutralizing anti-interleukin 10 (IL-10) antibodies. Moreover, soluble factors from BW/ST1LIF cells reduce cell proliferation but enhance the migratory responses of monocytes. In addition, these factors reverse the inhibitory effect of IFN-c on monocyte/macrophage motility. BW/ST1LIF cells also generate IFN-c-activated macrophages with enhanced IL-10 expression, but reduced tumor-necrosis factor alpha (TNF-a), CD14 and CD40 expression as well as impaired cytotoxic function. Additional assays performed in the presence of neutralizing anti-IL-10 antibodies and exogenous IL-10 demonstrate that reduced macrophage cytotoxicity and proliferation, but increased cell motility result from the ability of trophoblast IL-10 to sustain Stat3 activation and suppress IFN-c-induced Stat1 activation. These in vitro studies are the first to describe the regulatory role of the LIF-trophoblast-IL-10 axis in the process of macrophage activation in response to pro-inflammatory cytokines.
U sually caused by progressive atherosclerosis and associated thrombosis, peripheral arterial disease (PAD) is characterized by a reduced blood flow to the lower limbs, leading to ischemia during physical exertion and intermittent claudication as clinical presentation. 1 Intermittent claudication, classically defined by pain and muscle cramps when walking, results in a greatly reduced walking capacity and functional status. 2,3 This functional decline lowers patient quality of life and willingness to engage in physical activity, which further worsens the risk of cardiovascular disease 4 and premature mortality. 5 For these reasons, improving walking capacity is now considered a priority for the treatment of PAD. 6 Aerobic exercise, typically in the form of walking, is considered a first-line treatment in this population. 7 Scientific evidence supports the existing guidelines that recommend ≥3/wk of supervised exercise sessions of intermittent walking, according to the pain threshold (3-4/5), for 30-45 min/ session, for ≥3 mo. [7][8][9] Recent meta-analyses and clinical trials have shown an increase in maximum walking distance (MWD) on treadmill tests after supervised exercise therapy (SET) in patients with symptomatic PAD. [10][11][12][13] Although home-based exercise has shown encouraging results, the magnitude of these results was inferior to SET. 14 According to the American Heart Association, the optimal SET modality still needs to be determined for patients with PAD. 15 Accumulating data indicate that other types of SET, such as Nordic walking, underwater exercise, and resistance training, could also be effective in improving walking capacity in patients with PAD. [16][17][18][19] Recently, a meta-analysis 8 suggested that other modes of exercise (without any distinction between them) could improve walking ability similar to supervised intermittent walking. Although this
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.