Sang Chul Han

Fermented fish oil suppresses T helper 1/2 cell response in a mouse model of atopic dermatitis via generation of CD4+CD25+Foxp3+ T cells

BackgroundAllergic skin inflammation such as atopic dermatitis (AD), which is characterized by pruritus and inflammation, is regulated partly through the activity of regulatory T cells (Tregs). Tregs play key roles in the immune response by preventing or suppressing the differentiation, proliferation and function of various immune cells, including CD4+ T cells. Recent studies report that fermentation has a tremendous capacity to transform chemical structures or create new substances, and the omega-3 polyunsaturated fatty acids (n-3 PUFAs) in fish oil can reduce inflammation in allergic patients. The beneficial effects of natural fish oil (NFO) have been described in many diseases, but the mechanism by which fermented fish oil (FFO) modulates the immune system and the allergic response is poorly understood. In this study, we produced FFO and tested its ability to suppress the allergic inflammatory response and to activate CD4+CD25+Foxp3+ Tregs.ResultsThe ability of FFO and NFO to modulate the immune system was investigated using a mouse model of AD. Administration of FFO or NFO in the drinking water alleviated the allergic inflammation in the skin, and FFO was more effective than NFO. FFO treatment did increase the expression of the immune-suppressive cytokines TGF-β and IL-10. In addition, ingestion of FFO increased Foxp3 expression and the number of CD4+CD25+Foxp3+ Tregs compared with NFO.ConclusionsThese results suggest that the anti-allergic effect of FFO is associated with enrichment of CD4+CD25+ Foxp3+ T cells at the inflamed sites and that FFO may be effective in treating the allergic symptoms of AD.

Docosahexaenoic acid alleviates atopic dermatitis by generating tregs and IL-10/TGF-β-modified macrophages via a TGF-β-dependent mechanism

Regulatory T cells (Tregs) have key roles in the immune response by suppressing the differentiation and proliferation of various immune cells. The beneficial effects of docosahexaenoic acid (DHA) have been described for many diseases; however, the mechanism by which it modulates the immune system is poorly understood. Therefore, the aim of this study was to examine whether DHA suppresses allergic reactions and upregulates the generation of CD4(+)Foxp3(+) T cells. We also examined the effects of transfusing interleukin-10/transforming growth factor-β (TGF-β)-modified macrophages (M2 macrophages) treated with DHA into a mouse model of atopic dermatitis. Here, we show that administration of DHA upregulates the generation of TGF-β-dependent CD4(+) forkhead box protein 3 (Foxp3(+)) Tregs. DHA induced T-cell hypo-responsiveness and downregulated cytokines associated with T helper (Th)-1, Th2, and Th17 cells. The differentiation of Foxp3(+) Tregs into CD4(+) T cells was directly mediated by DHA-M2 macrophages, which deactivated effector macrophages and inhibited CD4(+) T-cell proliferation. DHA showed therapeutic effects in mice with experimental atopic dermatitis. These results show that DHA enhances the function of M2 macrophages and that the generation of Tregs effectively protects mice against an inflammatory immune disorder. Thus, DHA may be a useful therapeutic strategy for treating chronic inflammatory diseases.

Diphlorethohydroxycarmalol Inhibits Interleukin-6 Production by Regulating NF-κB, STAT5 and SOCS1 in Lipopolysaccharide-Stimulated RAW264.7 Cells

Diphlorethohydroxycarmalol (DPHC) is a phlorotannin compound isolated from Ishige okamuarae, a brown alga. This study was conducted to investigate the anti-inflammatory effect and action mechanism of DPHC in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. We found that DPHC strongly reduces the production of interleukin 6 (IL-6), but not that of tumor necrosis factor-alpha (TNF-α) induced by LPS. DPHC (12.5 and 100 μM) suppressed the phosphorylation and the nuclear translocation of NF-kappaB (NF-κB), a central signaling molecule in the inflammation process induced by LPS. The suppressor of cytokine signaling 1 (SOCS1) is a negative feedback regulator of Janus kinase (Jak)-signal transducer and activator of transcription (STAT) signaling. In this study, DPHC inhibited STAT5 expression and upregulated that of SOCS1 at a concentration of 100 μM. Furthermore, N-tosyl-l-phenylalanine chloromethyl ketone (TPCK) (a specific NF-κB inhibitor) and JI (a specific Jak2 inhibitor) reduced the production of IL-6, but not that of tumor necrosis factor-alpha (TNF-α) in LPS-stimulated RAW 264.7 macrophages. These findings demonstrate that DPHC inhibits IL-6 production via the downregulation of NF-κB and Jak2-STAT5 pathway and upregulation of SOCS1.

Anti-inflammatory amino acid derivatives from the ascidian Herdmania momus.

Four new amino acid derivatives, herdmanines A-D (1-4), were isolated from the marine ascidian Herdmania momus. Herdmanines A-C contain the unusual D-form of arginine. Compounds 3 and 4 had a moderate suppressive effect on the production of NO, with IC₅₀ values of 96 and 9 μM, respectively. These compounds were found to inhibit the mRNA expression of iNOS. The inhibitory activities on the production and mRNA expression of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 were evaluated.

The Chloroform Fraction of Carpinus tschonoskii Leaves Inhibits the Production of Inflammatory Mediators in HaCaT Keratinocytes and RAW264.7 Macrophages.

Inflammation is the immune system’s response to infection and injury-related disorders, and is related to pro-inflammatory factors (NO, PGE2, cytokines, etc.) produced by inflammatory cells. Atopic dermatitis (AD) is a representative inflammatory skin disease that is characterized by increasing serum levels of inflammatory chemokines, including macrophage-derived chemokine (MDC). Carpinus tschonoskii is a member of the genus Carpinus. We investigated the anti-inflammatory activity of C. tschonoskii by studying the effects of various solvent fractions prepared from its leaves on inflammatory mediators in HaCaT and RAW264.7 cells. We found that the chloroform fraction of C. tschonoskii inhibited MDC at both the protein and mRNA levels in HaCaT cells, acting via the inhibition of STAT1 in the IFN-γ signaling pathway. In addition, the chloroform fraction significantly suppressed the expression of inflammatory factors induced by lipopolysaccharide stimulation, except COX-2 and TNF-α. These results suggest that the chloroform fraction of C. tschonoskii leaves may include a component with potential anti-inflammatory activity.

The Inhibitory Effect of Premature Citrus unshiu Extract on Atopic Dermatitis In Vitro and In Vivo

Atopic dermatitis (AD) is a chronic, recurrent inflammatory skin disease that is associated with Th2 cellmediated allergy. The process that leads to infiltration of inflammatory cells into an AD lesion is remarkably dependent on various chemokines, especially TARC (thymus and activation-regulated chemokine/CCL17) and MDC (macrophage-derived chemokine/CCL22). Serum levels of these chemokines are over-expressed in AD patients. Citrus unshiu, which is known as Satsuma mandarin, has anti-oxidative, anti-inflammation, and anti-microviral activity. Therefore, we investigated the effect of EtOH extract of premature C. unshiu on AD. We did this using a DNCB-induced AD mouse model. We also tried to confirm an inhibitory effect for premature C. unshiu on the expression of inflammatory chemokines in IFN-γ and TNF-α stimulated HaCaT human keratinocytes. We found that extract of premature C. unshiu reduced DNCB-induced symptoms such as hyperkeratosis, increased skin thickness, and infiltrated mast cells, in our AD-like animal model. The extract decreased levels of IFN-γ and IL-4 in ConA-stimulated splenocytes isolated from DNCB-treated mice. Also, extract of premature C. unshiu inhibited mRNA expression and protein production of TARC and MDC through the inhibition of STAT1 phosphorylation. These results suggest that C. unshiu has anti-atopic activity by regulating inflammatory chemokines such as TARC and MDC.

External Application of Fermented Olive Flounder (Paralichthys olivaceus) Oil Alleviates Inflammatory Responses in 2,4-Dinitrochlorobenzeneinduced Atopic Dermatitis Mouse Model

Allergic skin inflammation such as atopic dermatitis (AD) is characterized by edema and infiltration with various inflammatory cells such as mast cells, basophils, eosinophils and T cells. Thymic stromal lymphopoietin (TSLP) is produced mainly by epidermal keratinocytes, as well as dermal fibroblasts and mast cells in the skin lesions of AD. Omega-3 polyunsaturated fatty acids in fish oil can reduce inflammation in allergic patients. Fermentation has a tremendous capacity to transform chemical structures. The antiinflammatory effects of fish oil have been described in many diseases, but the beneficial effects by which fermented olive flounder oil (FOF) modulates the allergic response is poorly understood. In this study, we produced FOF and tested its ability to suppress the various allergic inflammatory responses. The ability of FOF to modulate the immune system was investigated using a mouse model of AD. The FOF-treated group showed significantly decreased immunoglobulin E (IgE) and histamine in serum. Also, the increased TSLP expression was significantly inhibited in the FOF group; the FOF-treated group was not appreciably different from the hydrocort cream treatment group. In addition, FOF treatment resulted in a smaller spleen size with reduced the thickness and length compared to the induction group. Splenocytes from mice treated with FOF produced significantly less IFN-γ, IL-4, T-box transcription factor (T-bet) and GATA binding protein 3 (GATA3) expression compared with the induction group. These results suggest that FOF may be effective in treating the allergic symptoms of AD. 5.

Sargachromanol G regulates the expression of osteoclastogenic factors in human osteoblast-like MG-63 cells

Bone diseases are characterized by the presence of pro-inflammatory cytokines that regulate bone turnover. The receptor activator of NF-κB ligand (RANKL) is a soluble osteoblast-derived protein that induces bone resorption through osteoclast differentiation and activation. Sargachromanol G (SG) was isolated from the brown algae Sargassum siliquastrum; SG has anti-osteoclastogenic activity, but its mechanism of action and its active components remain largely unknown. In the present study, we investigated the anti-osteoclastogenic effects of SG on the expression of interleukin-1β (IL-1β)-induced osteoclastogenic factors (PGE(2), COX-2, IL-6, OPG, and RANKL) in the human osteoblast cell line MG-63. We also examined the role of the nuclear factor-κB (NF-κB) and the mitogen-activated protein kinase (MAPK) signaling pathways in IL-1β-stimulated MG-63 cells. SG dose-dependently inhibited the production of osteoclastogenic factors in MG-63 cells. SG also inhibited phosphorylation of MAPK (ERK1/2, p38, and JNK) and NF-κB (p65, p50, and IκB-α). These results suggest that the anti-osteoporotic effect of SG may be because of the modulation of osteoclastogenic factors via suppression of MAPK and NF-κB activation.

Quercetagetin inhibits macrophage‐derived chemokine in HaCaT human keratinocytes via the regulation of signal transducer and activator of transcription 1, suppressor of cytokine signalling 1 and transforming growth factor‐β1

Inflammatory chemokines, such as macrophage‐derived chemokine (MDC/CCL22), are elevated in the serum and lesioned skin of patients with atopic dermatitis (AD), and are ligands for C‐C chemokine receptor 4, which is predominantly expressed on T helper 2 lymphocytes, basophils and natural killer cells. We have previously reported that quercetagetin has an inhibitory activity on inflammatory chemokines, which is induced by interferon (IFN)‐γ and tumour necrosis factor (TNF)‐α, occurring via inhibition of the signal transducer and activator of transcription 1 (STAT1) signal.