Bromelain treatment reduces CD25 expression on activated CD4+ T cells in vitro☆
Introduction
The hallmark of many immune mediated disorders is the dysregulated activation of T cells [1], [2]. Primary events in the activation of T cells are the presentation of an antigenic stimulus via an antigen presenting cell (APC) to the T cell [3] and augmentation by co-stimulatory signals (CD80, CD86) on the APC [4]. Following this unique interaction the T cell up-regulates activation markers such as CD25, the high affinity alpha chain of the IL-2 receptor [5]. Once IL-2 binds to CD25 it triggers a signaling cascade, resulting in T cell proliferation and additional IL-2 production. CD25 is constitutively expressed on CD4+ CD25+ Foxp3+ T regulatory cells, up-regulated on CD4+ T cells in response to antigen and a fraction of CD25 can be released in soluble form (sCD25) [6]. Increased levels of sCD25 have been shown to correlate with disease severity in individuals with allergic asthma [7]. Serum levels of sCD25 rise in accordance with the IL-2 receptor and are currently being investigated as biomarkers in allergy and asthma. Therapeutic interventions that target T cell mediated diseases are often designed to either boost (cancer, infectious diseases) or lower (autoimmune, allergy) the threshold of T cell activation via alteration of cell surface receptors.
A number of natural products such as essential fatty acids [8], Ginseng extracts [9], Curcumin [10] and Bromelain (EC 3.4.22.32) an extract from the common pineapple [11], have been identified as therapeutic targets for inflammation due to their ability to modulate T cell activation and expansion. Bromelain (Br) is a combination of proteins which contain cysteine protease activity [12]. Br has been shown to enhance the expression of CD11c and CD86 [13], [14] or suppress other surface markers such as CD44, B7-1, and CD80 [15], [16] on distinct cell populations in a variety of immunological systems. Br can modulate T cell production of inflammatory cytokines IL-4, IFN-γ [15], [16] and IL-13 [17] and down-regulate inflammatory responses in animal models of inflammatory bowel disease [18], experimental allergic encephalomyelitis [16] and allergic airway disease [19].
It has been previously demonstrated that Br inhibits downstream TCR signaling in CD4+ T helper cells [20] but the effect of Br on the expression of CD25 has been largely unexplored. The current study was designed to better understand the effect of Br on activated CD4+ T cells. In this manuscript we report that Br inhibits CD25 expression on activated CD4+ T cells, possibly via proteolytic cleavage.
Section snippets
Mice
Studies were performed on female C57BL/6J mice (Jackson Laboratory, Bar Harbor, ME), 8–10 weeks of age and weighing 17 to 20 g. Mice were housed conventionally in the animal facility at the University of Connecticut Health Center in accordance with institutional and Office of Laboratory Animal Welfare guidelines. All experimental procedures were approved by the institution's Center for Laboratory Animal Care.
Reagents
To directly reflect the natural products utilized in the marketplace, we chose a
Bromelain treatment reduces CD25 expression on activated CD4+ T cells
Previous work in our laboratory suggests that Br may reduce murine allergic asthma by preferentially modulating CD4+CD25+ T cells [17]. This experiment was designed to evaluate the effect of Br on CD25+ expression on activated CD4+ T cells, independent of TCR stimulus and therefore Br treatment was initiated on CD4+CD25+ T cells after the TCR stimulus was removed. As anticipated, CD25 expression was greatly increased on anti-CD3 stimulated naïve CD4++ T cells with 78% of the cells positive for
Discussion
We and others have previously demonstrated that Br exerts immuno-modulatory effects in CD4+ T cell mediated inflammation [16], [18], [21]. Our previous observations utilizing a murine model of ovalbumin-induced allergic asthma demonstrated that in vivo Br administration significantly reduced activated CD4+ T cells in particular CD4+CD25+ cells. There was no effect on the Foxp3 expressing T regulatory cells which constitutively express CD25. This observation led us to the current experiments
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2021, Leukemia ResearchCitation Excerpt :Another study demonstrated that bromelain effectively inhibited the regulation of CD25 surface molecules and blocked the expression of CD4+ T cells. Furthermore, bromelain inhibited the expression of ERK2 during the activation of T-cells [97]. Debnath and co-workers studied (in-vitro) the effect of bromelain in combination with peroxidase (BM-PR) against Dalton’s lymphoma (DLA) cells and reported that BM-PR significantly suppressed the cell-proliferation at a dose of 500 μg/mL after 72 h treatment.
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2018, Nonvitamin and Nonmineral Nutritional SupplementsDietary bromelain-C.3.4.22.32 supplementation improves performance and gut health in sows and piglets
2015, Livestock ScienceCitation Excerpt :Bromelain could modulate immune system function (Maurer, 2001), which may directly affect swine growth performance. Treatment of cells with bromelain causes decreased activation of CD4 (+) T cells and reduced expression of CD25 (Secor et al., 2009), which can explain the increased lymphocyte counts and immunity observed in lactating sows in the present study. Moreover, lactating sows fed the BR3 diet had increased milk protein, which could improve the IgG in the suckling piglets.
Increased proportion of CD4<sup>+</sup>CD25<sup>+</sup>Foxp3<sup>+</sup> regulatory T cells during early-stage sepsis in ICU patients
2013, Journal of Microbiology, Immunology and InfectionCitation Excerpt :It was previously shown in vivo and in vitro that stimulation with LPS increased the surface markers for Tregs, which indicates the proliferation and inhibition of apoptosis of these cells.14 CD25 could be produced by activated Tregs,15 and CD4+CD25+ T cells can express CD25 using certain enzymes (e.g., bromelain).16 We found that the CD25 levels in plasma were increased, as described in a previous study.17
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2013, Journal of Drug Delivery Science and Technology
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Grant support: This research was supported by NIH/AI R01 HL-43573, NIH/NCCAM FG32-AT001569, NIH/NCCAM K08 and Competitive Technologies Inc.