Inflammation triggers the activation of macrophages and neutrophils, leading to the production of mediators such as nitric oxide (NO), prostaglandin E2 (PGE2), inflammatory cytokines, and anti-inflammatory cytokines. Inflammatory cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) are considered biomarkers of inflammation. Research indicates that inflammation plays a role in the development of numerous illnesses. The pathological processes behind conditions like rheumatoid arthritis, inflammatory bowel disease, Alzheimer’s disease, and cardiovascular diseases involve chronic inflammation. Fucoidan, a complex polysaccharide found in brown algae and some marine invertebrates, has been documented to impact various stages of the inflammatory process.
This blog post will review the following article “Immunomodulatory and Anti-inflammatory Effects of Fucoidan: A Review.”The study focuses on the immunomodulatory and anti-inflammatory actions of fucoidan found in large algae, in addition to the models utilized to gauge these effects.
Previous studies reported that pretreatment with LPS reduced PGE2 secretion in RAW 264.7 cells. Furthermore, this polysaccharide inhibited the nuclear accumulation of the NF-κB p65 subunit and the degradation of IκBα. Fucoidan from Fucus vesiculosus also reduced the secretion of TNF-α and IL-1β in these cells and suppressed neutrophil infiltration, suggesting its potential to suppress the early stages of inflammation.
A separate study investigated how modified fucoidan influenced nitric oxide production in RAW264.7 macrophages stimulated by LPS. Methacrylated fucoidan reduced NO release and CD86 expression. CD86 is a costimulatory molecule in the interaction between antigen-presenting cells and T cells, and increased CD86 levels lead to enhanced immune responses. The anti-inflammatory cytokine IL-10 demonstrated a similar effect to fucoidan in terms of increasing CD86 levels following LPS and IFN-γ treatment.
Additionally, a study investigated the effects of a fucoidan fraction from Chnoospora minima on LPS (Lipopolysaccharides)-stimulated RAW 264.7 macrophages and found a dose-dependent inhibition of LPS-induced NO production (IC50 27.82 µg/mL), iNOS, and COX-2 expression. Fucoidan also suppressed the increased synthesis of PGE2 and inflammatory mediators such as TNF-α, IL-1β, and IL-6.
In a series of experiments on several compounds from the brown algae Sargassum horneri, HMWF suppressed the production of NO, PGE2, and the inflammatory cytokines TNF-α and IL-6 in LPS-treated mouse macrophage cell lines (RAW 264.7). Furthermore, crude polysaccharides that were obtained from cellulase enzyme digests have also demonstrated anti-inflammatory properties. This compound reduced the production of NO, PGE2, TNF-α, and IL-1β in LPS-stimulated RAW 264.7 cell lines. In this in vitro inflammation model, the expression of iNOS and COX2 was also suppressed. The researchers also observed downregulation of the NF-κB and MAPK signaling pathways.
Discoveries in recent research have clarified the processes behind the anti-inflammatory effects of fucoidan purified from Saccharina japonica, also recognized as Laminaria japonica. The authors reported that after applying fucoidan to LPS-stimulated RAW 264.7 macrophage cells, NO production, iNOS, and COX-2 expression were reduced. Compared to the control group of LPS-stimulated RAW 264.7 cells that were not treated, a reduction in TNF-α, IL-1β, and IL-6 levels was also noted. This study also showed that the anti-inflammatory effects of fucoidan are associated with the suppression of phosphorylation in the MAPK and NF-κB signaling pathways.
In response to pathogens entering the upper skin layers, keratinocytes, which are plentiful in the epidermis, generate inflammatory cytokines and chemokines. This process triggers skin inflammation, which can sometimes become chronic and lead to atopic dermatitis. IL-1β and IL-6, inflammatory cytokines originating from keratinocytes, are instrumental in the infiltration of inflammatory cells into tissues, the multiplication of keratinocytes, and the subsequent production of other cytokines by these cells. Treatment with fucoidan reduced the levels of IL-1β and IL-6 and suppressed the synthesis of inflammatory chemokines. Recent studies have reported, in the same in vitro model, a reduction in COX-2 activity and decreased production of PGE2, TNF-α, and IL-8 after treatment with kelp extract.
Fucoidan isolated from Laminaria Japonica reduced NO synthesis and iNOS expression in LPS-activated primary microglia. LPS-induced morphological changes in microglia were also suppressed. Elevated iNOS levels due to inflammation result in greater NO production, a process that can be modulated by intracellular signaling molecules and transcription factors, including nuclear factor NF-κB and activator protein (AP)-1. The anti-inflammatory effect of fucoidan is likely mediated through the p38 pathway. Another study focused on changes in cytokine levels in BV2 microglial cells after treatment with fucoidan derived from Fucus Vesiculosus. This sulfated polysaccharide significantly reduced the levels of NO, PGE2, IL-1β, and TNF-α in LPS-activated microglial cells. This anti-inflammatory action is linked to the suppression of the NF-κB, Akt, ERK, p38 MAPK, and JNK pathways.
The study found that low molecular weight fucoidan (LMWF) from Sargassum hemiphyllum reduced LPS-induced inflammation in Caco-2 human intestinal epithelial cell cultures. This sulfated polysaccharide reduced the levels of inflammatory cytokines TNF-α and IL-1β, and increased the levels of anti-inflammatory cytokines IL-10 and IFN-γ. The mechanism for the reduction in TNF-α and IL-1β levels suggests the involvement of inhibition of the NF-κB pathway. Fucoidan from Laminaria japonica and Fucus vesiculosus extract also reduced IL-8 levels in a Caco-2/RAW 264.7 co-culture system and Caco-2 cells, respectively.
Studies conducted on rodents and zebrafish embryos in living organisms have indicated that fucoidan’s anti-inflammatory properties might stem from reductions in blood glucose and serum levels of IL-1α, IL-1β, IL-6, IL-10, TNF-α, IFN-γ, PGE2, and TGF-β1. The findings point to a reduction in NO and ROS generation and iNOS expression. Furthermore, there’s a decrease in COX-2 gene expression and NF-κB signaling, along with suppressed neutrophil migration and a rise in IL-10.
Fucoidan, a purified compound from the brown alga Undaria pinnatifida, was found to activate human neutrophils and natural killer (NK) cells. It also stimulated the production of inflammatory cytokines such as IL-6, IL-8, and TNF-α, while simultaneously delaying the natural cell death (apoptosis) of these immune cells. Fucoidan from Fucus vesiculosus promoted dendritic cell maturation, cytotoxic T cell activation, Th1 immune responses, antibody production after antigen stimulation, and the production of memory T cells [76]. Fucoidans from Laminaria japonica, Laminaria cichorioides, and Fucus evanescens were also able to activate immune defenses.
Previous investigations have demonstrated that fucoidan’s interaction with Toll-like receptors (TLRs) results in enhanced cytokine and chemokine generation, as well as greater expression of MHC molecules. As a result, the activity of both specific and innate immune cells was enhanced. Toll-like receptors are part of the innate immune system, and substances that bind to TLRs activate the NF-κB signaling pathway. Fucoidan binds to TLR-2 and TLR-4, but not to TLR-5, enhancing the immune response. Studies in HSV-1 infected mice administered with fucoidan from Undaria pinnatifida reported activation of T cells and natural killer (NK) cells, as well as increased production of inflammatory cytokines.
Studies comparing the effects of fucoidans from Ascophyllum nodosum, Macrocystis pyrifera, Undaria pinnatifida, and Fucus vesiculosus demonstrated their ability to modulate the immune system. All fucoidans significantly increased the production of IL-6, IL-8, and TNF-α from purified human neutrophils. They also delayed apoptosis, with M. pyrifera and U. pinnatifida showing the most pronounced effects. Fucoidan from M. pyrifera was considered the most promising compound compared to the other three fucoidans due to its potential to promote neutrophil apoptosis delay, mouse NK cell activation, dendritic cell maturation, T cell immune response, antigen-specific antibody production, and memory T cell production.
The influence of fucoidan extracted from Nizamuddinia Zanardinii on mouse macrophage cell line RAW264.7 and NK-92 cells has been more recently assessed. One fraction obtained from the brown algae showed distinct immunostimulatory activity. This polysaccharide induced increased secretion of NO, TNF-α, IL-1β, and IL-6, as well as activation of NK cells, NF-κB, and MAPK signaling pathways, resulting in the release of TNF-α and IFN-γ [79]. Fucoidans from A. Nodosum and F. Vesiculosus also induced NO synthesis and cytokine production in RAW264.7 cells via activation of NF-κB and AP-1 signaling pathways.
The exposure of the skin to ultraviolet B (UVB) rays leads to the development of localized inflammation, presenting with observable swelling and the accumulation of leukocytes within the dermis. Low-dose UVB irradiation reduced the production of cytokines such as TNF-α, IL-4, IL-6, and IFN-γ in vitro, which may be related to immunosuppression. In vivo, a decrease in IFN-γ production in type 1 helper T cell immunity was also observed. CD4+ T cells are also involved in the immunosuppressive activity of UVB. UVB irradiation increased the production and release of TNF-α by keratinocytes and fibroblasts. Fucoidan from Undaria pinnatifida showed immunomodulatory properties, increasing reduced IFN-γ levels. It also reduced edema and leukocyte migration to the skin. Despite this, their findings indicated no substantial disparities in IL-4, IL-6, and TNF-α levels, or NF-κB expression, within the experimental mice.
In summary, pending confirmation from human studies, fucoidan shows encouraging signs of being a natural therapeutic agent capable of treating, slowing the progression of, and preventing the onset of symptoms related to inflammatory and immune system disorders.
Source: Polymers (Basel). 2020 Oct 13;12(10):2338. doi: 10.3390/polym12102338