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, 147 (1), 155-63

Resveratrol and Curcumin Suppress Immune Response Through CD28/CTLA-4 and CD80 Co-Stimulatory Pathway

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Resveratrol and Curcumin Suppress Immune Response Through CD28/CTLA-4 and CD80 Co-Stimulatory Pathway

S Sharma et al. Clin Exp Immunol.

Abstract

The role of resveratrol and curcumin is well documented in cancer, inflammation, diabetes and various other diseases. However, their immunosuppressive action on T cells, B cells and macrophages is not well documented. In the present study, we have ascertained the effect of resveratrol and curcumin on T and B cells and macrophages. The most striking findings were that both resveratrol and curcumin suppressed the activity of T and B cells and macrophages, as evidenced by significant inhibition in proliferation, antibody production and lymphokine secretion. Interestingly, curcumin imparted immunosuppression by mainly down-regulating the expression of CD28 and CD80 and up-regulating CTLA-4. Resveratrol also functioned by decreasing the expression of CD28 and CD80, as well as by augmenting the production of interleukin (IL)-10.

Figures

Fig. 1
Fig. 1
Effect of resveratrol and curcumin on the proliferation of concanavalin A (ConA)-stimulated lymphocytes. ConA-stimulated lymphocytes were cultured with different concentrations (1, 5, 10, 20 μM) of resveratrol (RVT) and curcumin (CMN). After 72 h of incubation, [3H]-thymidine was added and the cells were harvested 16 h later and radioactivity incorporated was measured. As a control, cells + medium, cells + RVT/CMN could not generate more than 5000 counts per minute (cpm). *P < 0·05 compared to cells cultured with ConA. The data are the mean ± standard error (s.e.) of triplicate determinants.
Fig. 2
Fig. 2
Effect of resveratrol (RVT) and curcumin (CMN) on interferon (IFN)-γ and interleukin (IL)-4 production. RVT and CMN were added in different concentrations (1,5, 10, 20 μM) to concanavalin A (ConA)-stimulated lymphocytes. The supernatants were collected after 48 h and lymphokines were measured by enzyme-linked immunosorbent assay (ELISA). All the data were calculated as pg/ml of IFN-γ (a) and IL-4 (b) as computed by comparison with the standard curve using recombinant lymphokines. Data expressed are the mean ± standard error (s.e.) from triplicate samples. *P < 0·05 compared to the cytokines release by ConA-treated cells.
Fig. 3
Fig. 3
Effect of resveratrol (RVT) and curcumin (CMN) on the proliferation of lipopolysaccharide (LPS)-stimulated lymphocytes. RVT and CMN were added in different concentrations (1, 5, 10, 20 μM) to LPS-stimulated lymphocytes. After 72 h of incubation, [3H]-thymidine (0·5 μCi/well) was added and the cells were harvested 16 h later and radioactivity incorporated was measured. As a control, cells + medium, cells + RVT/CMN, could not generate more than 5000 counts per minute (cpm). *P < 0·05 compared to cells cultured with LPS. The data are the mean ± standard error (s.e.) of triplicate determinants.
Fig. 4
Fig. 4
Effect of resveratrol (RVT) and curcumin (CMN) on IgG1 and IgG2a production by lymphocytes. RVT and CMN were cultured in different concentrations (1, 5, 10 and 20 μM) with lipopolysaccharide (LPS) (5 μg/ml)-stimulated lymphocytes. The supernatants were collected after 48 h and isotypes were measured by enzyme-linked immunosorbent assay (ELISA). All the data were calculated as pg/ml of IgG1 (a) and IgG2a (b) computed by comparison with the standard curve using standard IgG1 and IgG2a isotypes. Data expressed are the mean ± standard error (s.e.) from triplicate samples. *P < 0·05 compared to the release in LPS treated cells.
Fig. 5
Fig. 5
Effect of resveratrol (RVT) and curcumin (CMN) on interleukin (IL)-1, IL-6, IL-10 and tumour necrosis factor (TNF)-α production. RVT and CMN were added in different concentrations (1, 5, 10, 20 μM) to lipopolysaccharide (LPS)-stimulated macrophages. The supernatants were collected after 48 h and cytokines were measured. All the data were calculated as pg/ml of IL-1 (a), IL-6 (b), TNF-α (c) and IL-10 (d), as computed by comparison with the standard curve using recombinant cytokines. Data expressed are the mean ± standard error (s.e.) from triplicate determinants. *P < 0·05 compared to the cytokines release by LPS-treated cells.
Fig. 6
Fig. 6
Effect of resveratrol (RVT) and curcumin (CMN) on the CD4+CD25+ T regulatory (Treg) cells. RVT and CMN were added in different concentrations (1, 5, 10, 20 μM) to concanavalin A (ConA)-stimulated lymphocytes and CD4+ and CD25+ were enumerated by phycoerythrin (PE)-labelled anti-CD4 and fluorescein isothiocyanate (FITC)-labelled anti-CD25 antibodies. The CD4+ CD25+ Treg cells were analysed by flowcytometer and the data representing the bar diagrams are expressed as percentage positive CD4+ CD25+ cells calculated, taking into consideration the ConA-treated cells as 100%. The data shown are from duplicate determinations.
Fig. 7
Fig. 7
Effect of resveratrol (RVT) and curcumin (CMN) on the expression of CD28 and CTLA-4. RVT and CMN were added in different concentrations (1,5, 10, 20 μM) to concanavalin A (ConA)-stimulated lymphocytes and the expression of CD28 and CTLA-4 was monitored on CD4+ T cells using phycoerythrin (PE)-labelled anti-CD4+ antibodies, cychrome (Cy)-labelled anti-CD28 and fluorescein isothiocyanate (FITC)-labelled anti-CTLA-4 antibodies. The expression was analysed by flowcytometer. The histograms indicate gated (R1) population of lymphocytes (a), gated (R2) population of CD4 cells (b), expression of CD28 (c) and CTLA-4 (d) on CD4+ T cells cultured with ConA (dotted line) and 20 μM of RVT and CMN (solid lines). The data shown in parentheses depict mean fluorescence intensity (MFI). The CD28 and CTLA-4 data shown as bar diagrams are expressed as the MFI (mean ± standard error (s. e.) of the cells cultured with different doses (1–20 μM) of RVT and CMN (e–h). The data shown are from triplicate determinants. *P < 0·05 compared to ConA-treated cells.
Fig. 8
Fig. 8
Effect of resveratrol (RVT) and curcumin (CMN) on the expression of CD80 and CD40. RVT and CMN were added in different concentrations (1, 5, 10, 20 μM) to lipopolysaccharide (LPS)-stimulated macrophages and the expression of CD80 and CD40 was monitored using cychrome (Cy)-labelled anti-CD80 and fluorescein isothiocyanate (FITC)-labelled anti-CD40 antibodies. The expression was analysed by flowcytometer and the histograms indicate expression of CD80 (a) and CD40 (b) on the cells cultured with LPS (dotted line) and 20 μM of RVT and CMN (solid lines). The data shown in parentheses depict mean fluorescence intensity (MFI). The CD80 and CD28 data shown as bar diagrams are expressed as the MFI (mean ± standard error (s. e.) of the cells cultured with different doses (1–20 μM) of RVT and CMN (c–f). *P < 0·05 compared to the LPS-treated cells.
Fig. 9
Fig. 9
Cumulative effect of resveratrol (RVT) and curcumin (CMN) on proliferation and cytokine secretion by T cells. Equal concentrations (20 μM) of RVT and CMN were cultured separately or in combination with concanavalin A (ConA)-stimulated lymphocytes. The culture conditions for proliferation and lymphokines secretion were the same as stated in the legends to Figs 1 and 2. The data are the mean ± standard error (s.e.) of triplicate determinants for proliferation (a), interferon (IFN)-γ (b) and IL-4 (c) secretion. *P < 0·05 compared to cells cultured with ConA.
Fig. 10
Fig. 10
Effect of resveratrol (RVT) and curcumin (CMN) on cell viability. The cells were cultured with different concentrations (1, 5, 10, 20 μM) of RVT and CMN. Viability was measured after 6 h of culture by MTT. Values are expressed as mean ± standard error (s.e.) from triplicate samples. Percentage viability of the cells is taken as 100% in control and calculated for viability in the drug-treated cultures.

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