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Oral administration of nano-emulsion curcumin in mice suppresses inflammatory-induced NFκB signaling and macrophage migration.

Young NA, Bruss MS, Gardner M, Willis WL, Mo X, Valiente GR, Cao Y, Liu Z, Jarjour WN, Wu LC - PLoS ONE (2014)

Bottom Line: Here, we confirm the immunosuppressive effects of NEC in vivo and further examine its molecular mechanisms to better understand therapeutic potential.Administration of NEC by oral gavage resulted in a reduction of blood monocytes, decreased levels of both TLR4 and RAGE expression, and inhibited secretion of MCP-1.These data demonstrate that curcumin can suppress inflammation by inhibiting macrophage migration via NFκB and MCP-1 inhibition and establish that NEC is an effective therapeutic formulation to increase the bioavailability of curcumin in order to facilitate this response.

View Article: PubMed Central - PubMed

Affiliation: Division of Rheumatology and Immunology, Wexner Medical Center at The Ohio State University, Columbus, Ohio, United States of America; Department of Internal Medicine, Wexner Medical Center at The Ohio State University, Columbus, Ohio, United States of America.

ABSTRACT
Despite the widespread use of curcumin for centuries in Eastern medicine as an anti-inflammatory agent, its molecular actions and therapeutic viability have only recently been explored. While curcumin does have potential therapeutic efficacy, both solubility and bioavailability must be improved before it can be more successfully translated to clinical care. We have previously reported a novel formulation of nano-emulsion curcumin (NEC) that achieves significantly greater plasma concentrations in mice after oral administration. Here, we confirm the immunosuppressive effects of NEC in vivo and further examine its molecular mechanisms to better understand therapeutic potential. Using transgenic mice harboring an NFκB-luciferase reporter gene, we demonstrate a novel application of this in vivo inflammatory model to test the efficacy of NEC administration by bioluminescent imaging and show that LPS-induced NFκB activity was suppressed with NEC compared to an equivalent amount of curcumin in aqueous suspension. Administration of NEC by oral gavage resulted in a reduction of blood monocytes, decreased levels of both TLR4 and RAGE expression, and inhibited secretion of MCP-1. Mechanistically, curcumin blocked LPS-induced phosphorylation of the p65 subunit of NFκB and IκBα in murine macrophages. In a mouse model of peritonitis, NEC significantly reduced macrophage recruitment, but not T-cell or B-cell levels. In addition, curcumin treatment of monocyte derived cell lines and primary human macrophages in vitro significantly inhibited cell migration. These data demonstrate that curcumin can suppress inflammation by inhibiting macrophage migration via NFκB and MCP-1 inhibition and establish that NEC is an effective therapeutic formulation to increase the bioavailability of curcumin in order to facilitate this response.

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Curcumin labels monocytes and inhibits macrophage migration in human cells.A, Human cell lines Jurkat, Clone E6-1 and THP-1 were cultured in complete RPMI medium, supplemented with various amounts of curcumin or vehicle, and analyzed by FACS. Representative results are shown. B, THP-1 (top) and primary human monocyte derived macrophages (bottom) were treated with the indicated concentrations of curcumin and cell viability was measured over time by MTT assay. Values are expressed as fold changes relative to initial baseline levels. C, THP-1 cells were differentiated into macrophages and isolated by adherence to culture plates. Scratch assays were performed on adherent cells with or without curcumin to measure cell migration. Representative images (left) and migrated cell counts (right). D, Primary macrophages were isolated from healthy human blood samples (n = 4) and subjected to migration assays with and without curcumin (20 µM) for the indicated time. Representative images (left) and relative fold changes of migrated cells (right) are shown. Original magnification X 40. *  =  p≤0.05 versus vehicle. n.s.  =  not significant versus vehicle.
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pone-0111559-g006: Curcumin labels monocytes and inhibits macrophage migration in human cells.A, Human cell lines Jurkat, Clone E6-1 and THP-1 were cultured in complete RPMI medium, supplemented with various amounts of curcumin or vehicle, and analyzed by FACS. Representative results are shown. B, THP-1 (top) and primary human monocyte derived macrophages (bottom) were treated with the indicated concentrations of curcumin and cell viability was measured over time by MTT assay. Values are expressed as fold changes relative to initial baseline levels. C, THP-1 cells were differentiated into macrophages and isolated by adherence to culture plates. Scratch assays were performed on adherent cells with or without curcumin to measure cell migration. Representative images (left) and migrated cell counts (right). D, Primary macrophages were isolated from healthy human blood samples (n = 4) and subjected to migration assays with and without curcumin (20 µM) for the indicated time. Representative images (left) and relative fold changes of migrated cells (right) are shown. Original magnification X 40. *  =  p≤0.05 versus vehicle. n.s.  =  not significant versus vehicle.

Mentions: The molecular structure of curcumin exhibits detectable fluorescent properties that can be exploited to measure cellular binding and uptake [27], [28]. Here, curcumin was added to T-lymphocyte (Jurkat, Clone E6-1) or monocyte (THP-1) derived human cell lines and was detected by flow cytometry. Cells were treated with increasing concentrations of curcumin for 10 min or 24 h and washed before FACS analysis. Although Jurkat cells did not produce a detectable response with curcumin that differed from vehicle treatment at any concentration after 10 min or 24 h, THP-1 cells were labeled with curcumin in a dose-dependent manner at both time points (Figure 6A). FACS plots revealed that 10 min of curcumin treatment of THP-1 cells resulted in an enhanced signal at every concentration (Figure 6A). Furthermore, despite very modest increases at lesser concentrations, considerably higher signals were obtained with both 20 µM and 30 µM curcumin after 24 h (Figure 6A).


Oral administration of nano-emulsion curcumin in mice suppresses inflammatory-induced NFκB signaling and macrophage migration.

Young NA, Bruss MS, Gardner M, Willis WL, Mo X, Valiente GR, Cao Y, Liu Z, Jarjour WN, Wu LC - PLoS ONE (2014)

Curcumin labels monocytes and inhibits macrophage migration in human cells.A, Human cell lines Jurkat, Clone E6-1 and THP-1 were cultured in complete RPMI medium, supplemented with various amounts of curcumin or vehicle, and analyzed by FACS. Representative results are shown. B, THP-1 (top) and primary human monocyte derived macrophages (bottom) were treated with the indicated concentrations of curcumin and cell viability was measured over time by MTT assay. Values are expressed as fold changes relative to initial baseline levels. C, THP-1 cells were differentiated into macrophages and isolated by adherence to culture plates. Scratch assays were performed on adherent cells with or without curcumin to measure cell migration. Representative images (left) and migrated cell counts (right). D, Primary macrophages were isolated from healthy human blood samples (n = 4) and subjected to migration assays with and without curcumin (20 µM) for the indicated time. Representative images (left) and relative fold changes of migrated cells (right) are shown. Original magnification X 40. *  =  p≤0.05 versus vehicle. n.s.  =  not significant versus vehicle.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4219720&req=5

pone-0111559-g006: Curcumin labels monocytes and inhibits macrophage migration in human cells.A, Human cell lines Jurkat, Clone E6-1 and THP-1 were cultured in complete RPMI medium, supplemented with various amounts of curcumin or vehicle, and analyzed by FACS. Representative results are shown. B, THP-1 (top) and primary human monocyte derived macrophages (bottom) were treated with the indicated concentrations of curcumin and cell viability was measured over time by MTT assay. Values are expressed as fold changes relative to initial baseline levels. C, THP-1 cells were differentiated into macrophages and isolated by adherence to culture plates. Scratch assays were performed on adherent cells with or without curcumin to measure cell migration. Representative images (left) and migrated cell counts (right). D, Primary macrophages were isolated from healthy human blood samples (n = 4) and subjected to migration assays with and without curcumin (20 µM) for the indicated time. Representative images (left) and relative fold changes of migrated cells (right) are shown. Original magnification X 40. *  =  p≤0.05 versus vehicle. n.s.  =  not significant versus vehicle.
Mentions: The molecular structure of curcumin exhibits detectable fluorescent properties that can be exploited to measure cellular binding and uptake [27], [28]. Here, curcumin was added to T-lymphocyte (Jurkat, Clone E6-1) or monocyte (THP-1) derived human cell lines and was detected by flow cytometry. Cells were treated with increasing concentrations of curcumin for 10 min or 24 h and washed before FACS analysis. Although Jurkat cells did not produce a detectable response with curcumin that differed from vehicle treatment at any concentration after 10 min or 24 h, THP-1 cells were labeled with curcumin in a dose-dependent manner at both time points (Figure 6A). FACS plots revealed that 10 min of curcumin treatment of THP-1 cells resulted in an enhanced signal at every concentration (Figure 6A). Furthermore, despite very modest increases at lesser concentrations, considerably higher signals were obtained with both 20 µM and 30 µM curcumin after 24 h (Figure 6A).

Bottom Line: Here, we confirm the immunosuppressive effects of NEC in vivo and further examine its molecular mechanisms to better understand therapeutic potential.Administration of NEC by oral gavage resulted in a reduction of blood monocytes, decreased levels of both TLR4 and RAGE expression, and inhibited secretion of MCP-1.These data demonstrate that curcumin can suppress inflammation by inhibiting macrophage migration via NFκB and MCP-1 inhibition and establish that NEC is an effective therapeutic formulation to increase the bioavailability of curcumin in order to facilitate this response.

View Article: PubMed Central - PubMed

Affiliation: Division of Rheumatology and Immunology, Wexner Medical Center at The Ohio State University, Columbus, Ohio, United States of America; Department of Internal Medicine, Wexner Medical Center at The Ohio State University, Columbus, Ohio, United States of America.

ABSTRACT
Despite the widespread use of curcumin for centuries in Eastern medicine as an anti-inflammatory agent, its molecular actions and therapeutic viability have only recently been explored. While curcumin does have potential therapeutic efficacy, both solubility and bioavailability must be improved before it can be more successfully translated to clinical care. We have previously reported a novel formulation of nano-emulsion curcumin (NEC) that achieves significantly greater plasma concentrations in mice after oral administration. Here, we confirm the immunosuppressive effects of NEC in vivo and further examine its molecular mechanisms to better understand therapeutic potential. Using transgenic mice harboring an NFκB-luciferase reporter gene, we demonstrate a novel application of this in vivo inflammatory model to test the efficacy of NEC administration by bioluminescent imaging and show that LPS-induced NFκB activity was suppressed with NEC compared to an equivalent amount of curcumin in aqueous suspension. Administration of NEC by oral gavage resulted in a reduction of blood monocytes, decreased levels of both TLR4 and RAGE expression, and inhibited secretion of MCP-1. Mechanistically, curcumin blocked LPS-induced phosphorylation of the p65 subunit of NFκB and IκBα in murine macrophages. In a mouse model of peritonitis, NEC significantly reduced macrophage recruitment, but not T-cell or B-cell levels. In addition, curcumin treatment of monocyte derived cell lines and primary human macrophages in vitro significantly inhibited cell migration. These data demonstrate that curcumin can suppress inflammation by inhibiting macrophage migration via NFκB and MCP-1 inhibition and establish that NEC is an effective therapeutic formulation to increase the bioavailability of curcumin in order to facilitate this response.

Show MeSH
Related in: MedlinePlus