Inflammatory bowel disease (IBD) is a group of disorders characterized by chronic inflammation within the gastrointestinal tract. It is a multifactorial disease associated with immune-cell mediated oxidative damage to the intestinal mucosa. There is no cure for IBD, but anti-cytokine therapy can limit target inflammation and disease progression. Unfortunately, many patients are nonresponsive or develop resistance to anti-cytokine therapy over time creating a need for new therapeutic agents. Metallothionein (MT) is a small, highly conserved stress response protein that has been shown to modulate the immune response as a pro-inflammatory agent, regulate divalent heavy metal homeostasis, and act as a reactive metabolite scavenger. Our research, as well as other groups studying MT, has described MT induction and release during IBD inflammatory stress response. The release of MT results in activation of inflammatory responses leading to progressive inflammation and subsequent expansion of MT synthesis. A monoclonal antibody specific for MT has been used in murine models of IBD and should only target the extracellular pool of MT, thus representing a novel therapeutic approach to this disease.
Metallothioneins (MTs) are small molecular weight stress response proteins that play a central role as reservoir of essential divalent heavy metal cations such as zinc and copper, and also can diminish the effects of toxic heavy metals such as mercury and cadmium. Historically, MT has been considered to be an intracellular protein with roles to play in the management of heavy metals, as a regulator of cellular redox potential, and as a buffer of free radicals. Our recent studies have highlighted immunomodulatory role of MT in inflammatory diseases and also in the progression of metastatic cell movement. Hence, manipulation and detection of MT is essential for its possible use as a diagnostic and in therapeutic interventions of chronic inflammation. This review describes procedures used to detect MT using techniques such as western immunoblot, competition ELISA, flow cytometry and immunohistochemistry. Additionally, it also describes the use of a colorimetric cell proliferation assay (CellTiter 96 AQ One Solution/MTS) to study the proliferative effect of MT. © 2017 by John Wiley & Sons, Inc.
The opportunistic pathogen Pseudomonas aeruginosa expresses a small molecular weight, cysteine-rich protein (PmtA), identified as a metallothionein (MT) protein family member. The MT family proteins have been well-characterized in eukaryotes as essential for zinc and copper homeostasis, protection against oxidative stress, and the ability to modify a variety of immune activities. Bacterial MTs share sequence homology, antioxidant chemistry, and heavy metal-binding capacity with eukaryotic MTs, however, the impact of bacterial MTs on virulence and infection have not been well-studied. In the present study, we investigated the role of PmtA in P. aeruginosa PAO1 using a PmtA-deficient strain (ΔpmtA). Here we demonstrated the virulence factor, pyocyanin, relies on the expression of PmtA. We showed that PmtA may be protective against oxidative stress, as an alternative antioxidant, glutathione, can rescue pyocyanin expression. Furthermore, the expression of phzM, which encodes a pyocyanin precursor enzyme, was decreased in the ΔpmtA mutant during early stationary phase. Upregulated pmtA expression was previously detected in confluent biofilms, which are essential for chronic infection, and we observed that the ΔpmtA mutant was disrupted for biofilm formation. As biofilms also modulate antibiotic susceptibility, we examined the ΔpmtA mutant susceptibility to antibiotics and found that the ΔpmtA mutant is more susceptible to cefepime and ciprofloxacin than the wild-type strain. Finally, we observed that the deletion of pmtA results in decreased virulence in a waxworm model. Taken together, our results support the conclusion that PmtA is necessary for the full virulence of P. aeruginosa and may represent a potential target for therapeutic intervention.
Natural killer (NK) cells have a dual role in human reproduction for maternal-fetal tolerance and protection from infection. During the ovarian cycle and pregnancy, peripheral NK (pNK) and uterine NK (uNK) cells dynamically change their proportions and cytotoxicities to prepare and accommodate invading trophoblast and maintain pregnancy. However, dysregulated pNK and uNK cell proportions and cytotoxic activities have been associated with aberrant spiral artery remodeling and trophoblast invasion, leading to implantation failures and recurrent pregnancy losses (RPLs). This review will focus on the role of NK cells in RPLs reviewing the ontogeny of NK cells, changes in pNK and uNK cell levels, and activities during the ovarian cycle, normal pregnancy, and RPL. In addition, the immunopathological role of NK cells in endometrial/decidual vascular development and killer immunoglobin-like receptor (KIR) and human leukocyte antigen (HLA)-C interactions are discussed.
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