Effects of vitamin D on immune disorders with special regard to asthma, COPD and autoimmune diseases: a short review.

This paper reviews the recent data on the role of vitamin D (VD) in the genesis of various immunological disorders. It inhibits immune reactions in general, but it enhances the transcription of 'endogenous antibiotics' such as cathelicidin and defensins. VD inhibits the genesis of both Th1- and Th2-cell mediated diseases. The pleiotropic character VD-induced effects are due to the altered transcription of hundreds of genes. VD supplementation in most related studies reduced the prevalence of asthma. Th1-dependent autoimmune diseases (e.g., multiple sclerosis, Type 1 diabetes, Crohn's disease, rheumatoid arthritis and so on) are also inhibited by VD due to inhibition of antigen presentation, reduced polarization of Th0 cells to Th1 cells and reduced production of cytokines from the latter cells. VD seems to also be a useful adjunct in the prevention of allograft rejection. Last but not least, VD supplementation may be useful in the prevention or adjunct treatment of chronic obstructive pulmonary disease.

Effect of vitamin A deficiency on the immune response in obesity.

Obesity has been associated with low-grade systemic inflammation and with micronutrient deficiencies. Obese individuals have been found to have lower vitamin A levels and lower vitamin A intake compared with normal-weight individuals. Vitamin A plays a major role in the immune function, including innate immunity, cell-mediated immunity and humoral antibody immunity. It has also been recognised recently that vitamin A has important regulatory functions. Vitamin A status has an important effect on the chronic inflammatory response. Vitamin A deficiency increases a T-helper type 1 (Th1) response, elevates levels of pro-inflammatory cytokines, increases the expression of leptin, resistin and uncoupling proteins (UCP) and promotes adipogenesis. The effect of vitamin A deficiency on obesity might be increasing the risk of fat deposition and also the risk of chronic inflammation associated with obesity. Supplementation with vitamin A in vitro and in animal models has been found to reduce concentrations of adipocytokines, such as leptin and resistin. In conclusion, vitamin A deficiency increases a Th1 response in the presence of obesity and thus, increases the inflammatory process involved in chronic inflammation and fat deposition. The metabolism of leptin and other adipocytokines may play a critical role in the effect of vitamin A deficiency in the inflammatory response observed in obesity.

N-Methyl-6, 7-dimethoxyisoquinolone in Annona squamosa twigs is the major immune modifier to elicit polarized Th1 immune response in BALB/c mice.

Annona squamosa (AS) has traditionally been used as ethnomedicine. We have earlier extracted and fractionated the twigs of AS based upon its bioactivity and observed its immune potentiating activity that was localized in its three fractions. Present communication deals with the phytochemical analysis and pharmacological investigation of the most active chloroform fraction that led to isolation and identification of a number of compounds whose structures were elucidated using 1D and 2D NMR spectroscopic analysis. Amongst the twelve pure compounds isolated, five compounds Lanuginosine (1), (+)-O-methylarmepavine (2), (+)-anomuricine (3), Isocorydine (4), and N-methyl-6, 7-dimethoxyisoquinolone (5) were evaluated in vivo for their immune modifier activities in BALB/c mice after oral administration at three log doses of 0.3, 1.0 and 3.0mg/kg for 14 consecutive days. Of these, three compounds (1, 2 and 5) showed dose dependent immune stimulating activity. However, the uppermost activity was noted in the compound N-methyl-6, 7-dimethoxyisoquinolone at the 3.0mg/kg oral dose. The activity was assessed in the form of increased splenic T and B cellular proliferation, up-regulated CD4+, CD8+ and CD19+ cell population and accentuation in the peritoneal macrophage function. The compound possibly acted modifying the expression of Th1- and Th2- cytokines via stimulation of pro-inflammatory Th1 cytokines IL-2 and IFN-γ. These results warrant the use of the above compounds as an efficient immune-stimulant or immune-adjuvant against diseases with immune suppression. The analogs of the compound may further be chemically synthesized to achieve desired immune modifying activity.

Triterpene esters from Uncaria rhynchophylla drive potent IL-12-dependent Th1 polarization.

Dendritic cells (DC) are key antigen-presenting cells that link innate and adaptive immunity and ultimately activate antigen-specific T cells. In the current study, we demonstrated that two triterpene esters, uncarinic acid C (1) and uncarinic acid D (2), which are isolated from the hooks of Uncaria rhynchophylla, activate phenotypic and cytokine production alterations in DC. We also show that 1 and 2 modulate human DC function in a fashion that favors Th1 cell polarization. The effect of 1 (E configuration at the 2' position) was approximately 20 times more potent than that of 2 (Z configuration at 2'). These results indicated that the configuration of the 2' double bond greatly effects activity. Thus, 1 and 2 may prove useful as DC-based vaccines for cancer immunotherapy.

Acupuncture and immune modulation.

Acupuncture is probably the most popular alternative therapy practiced in the United States, Europe and many Asian countries. It has been applied clinically for more than 5 thousand years according to the ancient oriental medical theory. A great deal of acupuncture research has been achieved, with particular efforts toward understanding the pain control effects. In addition to the analgesic effect of acupuncture, an increasing number of studies have demonstrated that acupuncture treatment can control autonomic nerve system functions such as blood pressure regulation, sphincter Oddi relaxation, and immune modulation. Although only a limited number of controlled studies have assessed the efficacy of acupuncture, increasing clinical evidences support that EA treatment is effective for various immunological diseases including allergic disorders, infections, autoimmune diseases and immunodifficiency-syndromes. This review will address the mechanism of acupuncture in modulating various immune responses and the relationship between acupuncture mediated immune regulation and neurological involvement.

Berberine differentially modulates the activities of ERK, p38 MAPK, and JNK to suppress Th17 and Th1 T cell differentiation in type 1 diabetic mice.

Berberine, an alkaloid derivative from Berberis vulgaris L., has been used extensively in traditional Chinese medicine to treat diarrhea and diabetes, but the underlying mechanisms for treating diabetes are not fully understood. Recent studies suggested that berberine has many beneficial biological effects, including anti-inflammation. Because type 1 diabetes is caused by T cell-mediated destruction of beta cells and severe islet inflammation, we hypothesized that berberine could ameliorate type 1 diabetes through its immune regulation properties. Here we reported that 2 weeks of oral administration of berberine prevented the progression of type 1 diabetes in half of the NOD mice and decreased Th17 and Th1 cytokine secretion. Berberine suppressed Th17 and Th1 differentiation by reducing the expression of lineage markers. We found that berberine inhibited Th17 differentiation by activating ERK1/2 and inhibited Th1 differentiation by inhibiting p38 MAPK and JNK activation. Berberine down-regulated the activity of STAT1 and STAT4 through the suppression of p38 MAPK and JNK activation, and it controlled the stability of STAT4 through the ubiquitin-proteasome pathway. Our findings indicate that berberine targets MAPK to suppress Th17 and Th1 differentiation in type 1 diabetic NOD mice. This study revealed a novel role of ERK in Th17 differentiation through down-regulation of STAT3 phosphorylation and RORgamma t expression.

Zinc in cancer prevention.

Essentiality of zinc for humans was discovered 45 yr ago. Deficiency of zinc is prevalent world wide in developing countries and may affect nearly 2 billion subjects. The major manifestations of zinc deficiency include growth retardation, hypogonadism in males, cell-mediated immune dysfunctions, and cognitive impairment. Zinc not only improves cell mediated immune functions but also functions as an antioxidant and anti-inflammatory agent. Oxidative stress and chronic inflammation have been implicated in development of many cancers. In patients with head and neck cancer, we have shown that nearly 65% of these patients were zinc deficient based on their cellular zinc concentrations. Natural killer (NK) cell activity and IL-2 generation were also affected adversely. Th2 cytokines were not affected. In our patients, zinc status was a better indicator of tumor burden and stage of disease in comparison to the overall nutritional status. Zinc status also correlated with number of hospital admissions and incidences of infections. NF-kappa B is constitutively activated in many cancer cells, and this results in activation of antiapoptotic genes, VEGF, cyclin DI, EGFR, MMP-9 and inflammatory cytokines. Zinc inhibits NF-kappa B via induction of A-20. Thus, zinc supplementation should have beneficial effects on cancer by decreasing angiogenesis and induction of inflammatory cytokines while increasing apoptosis in cancer cells. Based on the above, we recommend further studies and propose that zinc should be utilized in the management and chemoprevention of cancer.

Attenuated liver progenitor (oval) cell and fibrogenic responses to the choline deficient, ethionine supplemented diet in the BALB/c inbred strain of mice.

BACKGROUND/AIMS: Liver regeneration following chronic injury is associated with inflammation, the proliferation of liver progenitor (oval) cells and fibrosis. Previous studies identified interferon-gamma as a key mediator of oval cell proliferation. Interferon-gamma is known to regulate Th1 cell activities during immune challenge. Therefore, we hypothesised that progenitor cell-mediated regeneration is associated with a Th1 immune response. METHODS: C57Bl/6 (normal Th1 response) and BALB/c mice (deficient in Th1 signalling) were placed on a carcinogenic diet to induce liver injury, progenitor cell proliferation and fibrosis. RESULTS: Serum transaminases and mortality were elevated in BALB/c mice fed the diet. Proliferation of liver progenitor cells was significantly attenuated in BALB/c animals. The pattern of cytokine expression and inflammation differed between strains. Liver fibrosis and hepatic stellate cell activation were significantly inhibited in BALB/c mice compared to C57Bl/6. In addition, interferon-gamma knockout mice also showed reduced fibrosis compared to wild type. These findings are in contrast to published results, in which interferon-gamma is shown to be anti-fibrogenic. CONCLUSIONS: Our data demonstrate that the hepatic progenitor cell response to a CDE diet is inhibited in mice lacking Th1 immune signalling and further show that this inhibition is associated with reduced liver fibrosis.

Fms-like tyrosine kinase 3-based immunoprophylaxis against infection is improved by adjuvant treatment with anti-interleukin-10 antibody.

BACKGROUND: Fms-like tyrosine kinase 3 ligand (Flt3L) expands dendritic-cell populations in vivo and protects against microbial infection in healthy and immunocompromised hosts. Approaches for optimizing the protective effects of Flt3L in vivo are not well known.METHODS. BALB/c mice were treated for 9 days with 10 microg of recombinant (r) Flt3L with or without the addition of 250 microg of anti--interleukin (IL)-10 antibody on day 9. After Leishmania major infection, disease progression was determined by measuring cutaneous lesions. Production of IL-12 and interferon (IFN)- gamma were determined.RESULTS. Flt3L pretreatment increased the synthesis of CD40-inducible IL-12 p40 but not of bioactive p70. Coculture with anti--IL-10 antibody increased p70 production. Combined Flt3L and single-dose anti--IL-10 antibody pretreatment improved lesion cure rates from 40% to 87% relative to mice pretreated with rFlt3L only (P<.01, chi (2) test) and increased T helper 1 (Th1)--type cytokine production 4 weeks after infection but did not cure Rag-2-- and IFN- gamma -knockout BALB/c mice. Flt3L and anti-IL-10 antibody pretreatments increased frequencies of IL-12- and IFN- gamma -secreting cells 2 and 4 days after infection. Both natural killer and CD4(+) cells contributed to increased early IFN- gamma production.CONCLUSION. A single dose of anti--IL-10 antibody significantly improves Flt3L immunoprophylaxis against infection mediated by Th1-type adaptive responses.

The distinct effects of a butanol fraction of Bidens pilosa plant extract on the development of Th1-mediated diabetes and Th2-mediated airway inflammation in mice.

Bidens pilosa is claimed to be useful for immune or anti-inflammatory disorders; however, little scientific evidence has been published concerning its function. In this paper, immune disease mouse models were used to study the function of a butanol fraction of B.pilosa. We demonstrated treatment with the butanol fraction of B.pilosa ameliorated Th1 cell-mediated autoimmune diabetes in nonobese diabetic (NOD) mice but caused deterioration of Th2 cell-mediated airway inflammation induced by ovalbumin (OVA) in BALB/c mice. We next showed that Th2 cytokines (IL-4 and/or IL-5) increased but Th1 cytokine (IFN-gamma) decreased following injections with the butanol fraction of B.pilosa in both mouse strains. Accordingly, Th2 cytokine-regulated IgE production in mouse serum increased following treatment with this fraction. Finally, we found that the butanol fraction of B.pilosa inhibited Th1 cell differentiation but promoted Th2 cell differentiation. Taken together, the butanol fraction of B.pilosa has a dichotomous effect on helper T cell-mediated immune disorders, plausibly via modulation of T cell differentiation.

Differential requirements for the O-linked branching enzyme core 2 beta1-6-N-glucosaminyltransferase in biosynthesis of ligands for E-selectin and P-selectin.

Selectins are carbohydrate-binding adhesion molecules that play important roles in control of leukocyte traffic. Glycosyltransferases involved in selectin ligand biosynthesis include the alpha1,3-fucosyltransferases FucT-VII and FucT-IV, one or more sialyltransferases, and at least one O-linked branching enzyme. Previous studies have shown that core 2 beta1-6-N-glucosaminyltransferase (C2GlcNAcT-I; EC 2.4.1.102) is required for functional modification of PSGL-1, the leukocyte P-selectin ligand, but have been ambiguous on whether this enzyme is involved in E-selectin ligand formation. Using an attachment and rolling assay under defined shear flow in vitro, this study shows that C2GlcNAcT-I(-) lymphoid cells stably transfected with FucT-VII complementary DNA attach and roll well on E-selectin at 1.5 dynes/cm.(2) Further, attachment and rolling on P-selectin of neutrophils is sharply reduced and that of short- term polarized Th1 cells is virtually abolished, with leukocytes from C2GlcNAcT-I(-/-) mice. In contrast, both neutrophils and Th1 cells from C2GlcNAcT-I(-/-) mice attach and roll as well as wild-type cells on E-selectin. These results show that C2GlcNAcT-I is selectively required for biosynthesis of ligands for P-selectin, but is not essential for at least some E-selectin ligands. Distinct requirements for C2GlcNAcT-I in the formation of ligands for E-selectin versus P-selectin represents a novel level of regulation of expression of selectin ligands and lymphocyte traffic. (Blood. 2001;97:3806-3811)

Effect of seasonal exposure to pollen on nonspecific interleukin-4, interleukin-5, and interferon-gamma in vitro release by peripheral blood mononuclear cells from subjects with pollinosis.

The immune response to environmental allergens depends on both genetic and environmental factors. Allergen exposure triggers the activation of allergen-specific Th2 cells in allergic patients, as well as increased Th2-type cytokine mRNA expression and eosinophil recruitment. Nevertheless, different patterns of release of cytokines could explain the heterogeneity of atopic response. In our study, 25 patients with pollinosis and 15 healthy donors were selected to characterize their release of Th2 (interleukin [IL]-4 and IL-5) and Th1 (interferon-gamma [IFN-gamma]) cytokines, both during and outside the pollen season. Peripheral blood mononuclear cells from patients and controls were isolated, cultured in the presence of phorbol-12-myristate-13-acetate plus ionomycine, and phytohemagglutinin (PHA), and cytokine release was assessed by titration in the supernatants. Both IL-4 and IL-5 showed higher levels during than outside the pollen season in pollinic patients (P<0.05) after nonspecific stimuli, whereas IFN-gamma levels were significantly lower during than outside the pollen season only after culture with PHA. Significant differences were not observed in the control group. Our results are consistent with the hypothesis that release of cytokines by peripheral blood mononuclear cells from patients with pollinosis depends on environmental exposure to sensitizing pollens, and that influence can be revealed by in vitro nonspecific stimulation. Nevertheless, the heterogeneity in results suggests that the use of mitogens to assess Th1/Th2 dominance may need careful evaluation.