AUCTORES
Globalize your Research
Review Article | DOI: https://doi.org/10.31579/2768-0487/143
Laboratory for Immunology and Hematology Research, Rabin Medical Center, Hasharon Hospital, Petah-Tiqva, School of Medicine, Tel-Aviv University, Ramat Aviv, Israel.
*Corresponding Author: Meir Djaldetti. Laboratory for Immunology and Hematology Research, Rabin Medical Center, Hasharon Hospital, Petah-Tiqva, School of Medicine, Tel-Aviv University, Ramat Aviv, Israel.
Citation: Meir Djaldetti, (2024), Sulforaphane – A Potent Immunomodulator, Widely Available, Yet Underutilized, Journal of Clinical and Laboratory Research. 7(6); DOI:10.31579/2768-0487/143
Copyright: © 2024, Meir Djaldetti. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Received: 26 June 2024 | Accepted: 02 July 2024 | Published: 18 July 2024
Keywords: sulforaphane; mononuclear cells; cytokines; immunomodulation; immune response
Vegetables play a crucial role as an important source of nutrients in global culinary traditions. Their rich content of vitamins, minerals and polyphenols makes them valuable contributors to overall human health. Broccoli, a member of the Brassica oleracea family is widely recognized for its diverse culinary uses and its beneficial impact on various health conditions, such as acute and chronic inflammation, cardiovascular diseases, diabetes and cancer. Broccoli's health-promoting qualities stem from its high polyphenol content, of which sulforaphane (SFN) is the most notable. Due to its strong antioxidant properties and ability to increase the activity of peripheral blood mononuclear cells, SFN plays a significant role in immune system modulation. It plays a catalytic role in the production of inflammatory cytokines by monocytes and polarization from M1 to M2 macrophages. Acting on lymphocytes, which are integral part of the adaptive immune system, SFN triggers the production of antibodies and cytokines, while enhancing the generation of natural killer cells. Based on in vitro and animal research it appears that there is substantial number of studies to explain the ways SFN modulates the function of the immune cells. However, although the results indicate that we have an easily available therapeutic tool for a number of serious diseases, more research is needed to elucidate the effect of SFN in humans. It is the aim of the present review to summarize the knowledge about the immune properties of SFN with expectation that the content will serve as a challenge for further research.
Broccoli is a member of the Brassica oleracea family and has a lengthy history. Archeological evidence and seeds’ examinations imply that the countries in the Mediterranean region were the first to cultivate broccoli [1]. Its widespread in agriculture is due both to its nutritional value being a rich source of vitamins C and K, as well as most of the B group and folate [2]. Broccoli exerts beneficial activities against a wide range of illnesses such as cardiovascular and gastrointestinal diseases, diabetes, autism, rheumatoid arthritis, inflammatory and neurodegenerative conditions and a many types of cancers [3- 6]. In actuality, broccoli’s therapeutic properties stem from its thiocyanates, the most potent being sulforaphane (SFN) converted from glucoraphanin by myrosinase. It is ample documentation of SFN cytoprotective, antioxidant, anti-inflammatory and carcinopreventive effects [7]. Although SFN is highly concentrated in broccoli and its sprouts, it is also found in other cruciferous vegetables such as cauliflower and cabbage. In consumers of cruciferous vegetables SFN was able to suppress the production of pro-inflammatory cytokines by modulation of the toll-like receptor 4 (TLR4) [8]. The bioavailability, pharmacokinetics, dosage and toxicity of SFN have been extensively reviewed by Yagishita et al. [9]. The authors concluded that SFN is quickly absorbed with approximately 70% to 90
Monocytes play a crucial role in the immune system by producing cytokines, antibodies, and carrying out phagocytosis [21]. They are key players of the immune system and are actively involved in both acute and chronic inflammation. In cases of inflammation, researchers have focused on the ability of monocytes to differentiate into macrophages and their transition from classically activated M1 macrophages to alternatively activated M2, related to their ability to produce pro- and anti-inflammatory cytokines respectively [22]. At non-toxic concentrations of 10 µM SFN impeded the transition of M2 to M1 macrophages, thus inhibiting inflammatory markers’ expression such as COX2, the inducible nitric oxide synthase (iNOS), CD14, CD197 and the regulator of innate immune response IL-12p70. Furthermore, mitogen-activated protein kinases (MAPKs), which regulate various cell processes, including cell differentiation, were found to be implicated in the process of macrophage polarization. [23]. When human monocytes were treated with non-toxic concentrations of SFN it inhibited the release of pro-inflammatory cytokines IL-1β, IL-6, TNFα, and NF-kB as well as the signaling pathways (MAPK) [24]. It also inhibited the heme oxygenase inhibitor (HO), and the macrophage-activating lipopeptide 2 (MALP-2) which promote pro-inflammatory cytokine production and NF-kB activation, while increasing Nrf2 expression [25]. In the presence of SFN at concentrations of 10 and 50 µM human PBMC showed a reduced production
of the pro-inflammatory cytokines IL-6 and IL-1β and an increased differentiation towards dendritic cells [26].
Macrophages
Circulating monocytes that enter the tissues differentiate into macrophages and play a dominant role in innate immune responses by functioning as phagocytes and producing cytokines. When LPS stimulated Raw 264.7 macrophages were incubated with SFN at concentrations ranging between 0-50 µM, three was a significant inhibition of pro-inflammatory cytokines and nitric oxide (NO) expression though modulation of the inflammatory enzyme iNOS and activation of Nrf2/HO-1 transduction pathway [27]. In a mouse model and in vitro hyperoxia induced macrophage dysfunction SFN was able inhibit the oxidative stress by inducing Nrf2 generation and reducing the high mobility group box 1 protein (HNGB1) [28]. Furthermore, exposure of human macrophages to 25µM of SFN for 24 hours downregulated the production of inflammatory cytokines [29]. Qin et al. [30] discovered that administering of 50 mg/kg SFN to mice after hemorrhagic shock resulted in reduced inflammatory cytokine secretion by their splenic macrophages, along with increased Nrf2 activation, indicating a shift from M1 to M2 macrophage polarization. Treatment with 5 or 10 µM of SFN preserved the mitochondrial activity and maintained a normal tricarboxylic acid (TCA) cycle in bone marrow-derived M1 macrophages stimulated with LPS, 25 ng/ml [31]. Macrophages play a pivotal role in chronic inflammation linked to obesity. Administering 0.5 mg/kg of SFN to obese mice for six weeks, and treating RAW 264.7 LPS-stimulated macrophages with 2.5-5 µM of the polyphenol, resulted in the inhibition of iNOS, COX-2 expression, NO, TNFα, IL-1β, and IL-6 production [32]. Mouse bone marrow-derived M1 and M2 macrophages stimulated with LPS and IL-4, and IL-12 respectively treated with 10 µM of SFN, showed a shift towards M2 macrophages with a decrease of IL-12, IL-6 and TNFα secretion, as well as a simultaneous increase of low ability IgFc receptors (CS16/32) percentage in M-1 cells. The levels of heme oxidase (HO-10) and Nrf2 were also elevated. Conversely, SFN raised the levels of a few cytolytic enzymes such as YM1, Fizz1 and Arg1 in M2 macrophages [33]. On mouse LPS-stimulated peritoneal macrophages, it has been demonstrated that the SFN enantiomer (R)-S induces an immunomodulatory impact manifested by suppression of pro-inflammatory cytokines and enzymes, along with ROS species production. On the other hand Nrf-2/HO axis was activated whereas the inflammasome signaling pathways were inhibited [34]. It's interesting to note that inflammasome gene expression was inhibited in adipose tissue macrophages (ATP) exclusively, but it was reduced when 40 µM of SFN, TNFα and IL-1β were incubated with macrophages derived from healthy individuals and palmitic acid-stimulated ATP [35]. Notably, several members of the Brassica oleracea family are SFN and polysaccharides producers that have the potential to immunomodulate macrophage function. Thus, Sim et al. [36] have found that sprout extract from purple head broccoli (Brassica oleracea L., var. italica) contains more SFN compared to other species of the same family and when applied to LPS-stimulated RAW 264.7 macrophages, it significantly decreased the production of the pro-inflammatory cytokines IL-1β, IL-6, IL-1, TNFα and INOS.
Dendritic cells
Dendritic cells, together with macrophages, are an essential part of the innate immune system [37]. Furthermore, as antigen-presenting cells being specialized in activating the elements of the adaptive system they are actively involved in inflammatory responses and cancer cell development [38]. Their origin, development and relation to T cell immune responses have been reviewed by Puhr et al. [39]. Similar to macrophages and monocytes, dendritic cells react quickly to SFN. By reducing the expression of the activating markers CD80, CD83 and CD86, that are potent regulators of the T cells immune function, SFN restrains Th2 proliferation and decreases the secretion of the pro-inflammatory cytokines IL-9 and IL-12 [40].
Mouse bone marrow derived dendritic cells exposed to 0.3 µM of SFN showed inhibited TLR4-induced IL-12 and IL-23 cytokine generation by regulating the activity of TLR4-induced NF-kB factor. In addition, there was a significant hindrance to the development of Th1 and Th17 cells [41]. Similarly, SFN-treated porcine monocyte-derived dendritic cells demonstrated a controlled activity of TLR4-induced NF-kB transcription factor and suppressed histone deacetylases (HDACs) 6 and 10 [42,43]. Additional mechanisms by which SFN stimulates dendritic cells to increase T-cell activation include modulation of the regulatory proteins Janus kinase/transcription activator 3 (JAK/STAT3) leading to downregulation of the anti-apoptotic receptor B1-H1 and microRNA-signaling. Furthermore, SFN improved the activity of the dendritic cells by affecting their co-stimulatory molecules CD80 and CD83 [37]. Notably, as demonstrated in mice with induced colitis, broccoli-derived nanoparticles may also have an anti-inflammatory impact by activating dendritic cell adenosine monophosphate-activated protein kinase (AMPK) [44]. Results on the function of SFN on the immune activity of dendritic cells indicate that there is a challenge to mobilize them in the prevention of inflammatory processes and the immune defense.
The effect of SFN on lymphocytes
Being members of the antigen-presenting cells (APC), lymphocytes play a crucial role in the adaptive immune response. According to Checker et al. [45] treating mitogen stimulated T and B cells with SFN reduced their proliferation and upregulation as well as their ability to produce IL-2, IL-4, IL-6 and IFNγ cytokines. Furthermore, SFN stimulated the production of phosphoinositide kinase/protein kinase/glycogen synthase kinase 3β (PI3K/Akt/GSK-3β) expression leading to Nrf-2 activation. Human T cells are readily affected by SFN expressed by an increase in ROS species, suppression of the transcription factor RORyt and the T helper 17 (Th17) cells that are specialized in IL-17 and IL-22 secretion [46]. Mice with induced airway inflammation showed down-regulation of Th17 capacity to secrete pro-inflammatory cytokines overturned by Nrf2 activation after treatment with SFN. In addition, the corticosteroid resistance was inverted [47]. Activation of Nrf2 was the main cause for the beneficial effect of SFN when it was used in vitro and when given intragastric to mice with trichloroethylene-mediated necrotizing enterocolitis (NEC). At a dose of 20 mg/kg., it improved the colitis and the survival rate of the animals [48]. In another study with NEC mice the reduced the proportion of the helper Th17 to regulatory T cells (Th17/Treg cells’ ratio) and the levels of TLR4 and NF-kB, TNFα and IL-6 were decreased after treatment with SFN. Additionally, by controlling the PI3K/Akt/GSK-3β signaling pathway, both in vivo and in vitro, SFN reduced apoptosis [49].
The Th17/Treg cells’ ratio was observed to be downregulated in mice with B hepatitis following administration of 100 µM of SFN for 4 weeks [50] and in BTBR mice with idiopathic autism-like symptoms [51]. Notably it was found that SFN lessens the toxicity caused by cadmium. Compared to 69
Clearly Auctoresonline and particularly Psychology and Mental Health Care Journal is dedicated to improving health care services for individuals and populations. The editorial boards' ability to efficiently recognize and share the global importance of health literacy with a variety of stakeholders. Auctoresonline publishing platform can be used to facilitate of optimal client-based services and should be added to health care professionals' repertoire of evidence-based health care resources.
