Immunomodulatory activity of curcumin: suppression of lymphocyte proliferation, development of cell-mediated cytotoxicity, and cytokine production in vitro

https://doi.org/10.1016/j.bcp.2004.03.015Get rights and content

Abstract

Curcumin (diferuloylmethane), a major curcumanoid found in the spice turmeric, exhibits anti-inflammatory, anti-oxidant, and chemopreventive activities. However, the effect of curcumin on the development of T cell-mediated immunological responses largely remains unknown. In this study we have investigated the effect of curcumin on mitogen/antigen induced proliferation of splenic lymphocytes, induction of cytotoxic T lymphocytes (CTLs), lymphokine activated killer (LAK) cells, and the production of cytokines by T lymphocytes and macrophages. We found that mitogen, interleukin-2 (IL-2) or alloantigen induced proliferation of splenic lymphocytes, and development of cytotoxic T lymphocytes is significantly suppressed at 12.5–30 μmol/L curcumin. The generation of LAK cells at similar concentrations was less sensitive to the suppressive effect of curcumin compared to the generation of antigen specific CTLs. Curcumin irreversibly impaired the production of these immune functions, since lymphoid cells failed to respond to the activation signals following 8 h pretreatment with curcumin. Curcumin also inhibited the expression/production of IL-2 and interferon-gamma (IFN-γ) by splenic T lymphocytes and IL-12 and tumor necrosis factor-alpha (TNF-α) by peritoneal macrophages irreversibly. Curcumin inhibited the activation of the transcription factor nuclear factor kappaB (NF-κB) without affecting the levels of constitutively expressed NF-κB. The latter result suggests that curcumin most likely inhibits cell proliferation, cell-mediated cytotoxicity (CMC), and cytokine production by inhibiting NF-κB target genes involved in induction of these immune responses.

Introduction

Epidemiological and laboratory studies suggest that diet plays an important role in preventing the development of human cancers and other diseases [1], [2]. Several essential and nonessential dietary constituents found in common plant-derived foods have been recognized for their anticarcinogenic properties, and high dietary intake of dark green leafy vegetables, fruits, beans, and soy products has been linked to a low incidence of cancer and coronary heart disease [3], [4], [5], [6]. The disease-preventing effects of these foods are attributed in part to the presence of bioflavonoids, a group of naturally occurring polyphenolic substances [4]. Laboratory data have demonstrated that chemopreventive effects of some of these compounds are attributed to their strong anti-oxidant and anti-inflammatory properties, their ability to promote metal chelation, scavenging of free radicals, and detoxification of carcinogens [7], [8], [9]. At the cellular levels, these polyphenolic substances regulate a range of biochemical pathways that affect cell proliferation and signaling [6].

Curcumin (1,7-bis(4-hydroxy-3-methoxy phenyl)-1-6-heptadine-3,5-dione) is a naturally occurring yellow pigment found in the spice turmeric derived from the rhizome of the plant Curcuma longa. Besides its culinary appeal for color and flavor, turmeric or curcumin has been widely used for centuries in the Indian subcontinent for the treatment of a variety of illnesses such as common colds, coughs, jaundice, inflammatory bowl conditions, and arthritis [10]. Because of its ability to scavenge free radicals and inhibit inflammation [11], [12], curcumin has been investigated for cancer chemoprevention and tumor growth suppression. Curcumin was shown to prevent the development of cancers of the forestomach, duodenum, tongue, colon, and mammary glands in models of chemical carcinogenesis in mice and rats [13], [14], [15], [16], [17], [18], [19]. Exposure of tumor cell lines to curcumin in vitro has resulted in inhibition of cell proliferation or induction of apoptotic cell death [20], [21], [22], [23], [24].

We have previously shown that curcumin inhibits proliferation and induces apoptosis in several murine and human leukemia cell lines [25]. In addition, curcumin inhibited the IL-1α or tumor necrosis factor-alpha (TNF-α) induction of activation protein-1 (AP-1) and nuclear factor kappaB (NF-κB) in bone marrow stromal cells [26]. Recently, we also reported that curcumin sensitizes human prostate cancer cells for induction of apoptosis by TNF-α related apoptosis-inducing ligand (TRAIL) [27]. On the other hand, little is known about the effect of curcumin on the development of cell-mediated immune responses and production of cytokines involved in inflammation and antitumor immune responses. In the present study, we examined the effect of curcumin on mitogen/antigen-induced proliferation of murine lymphocytes, the development of cell-mediated cytotoxicity (CMC), and production of cytokines by lymphocytes and macrophages.

Section snippets

Agents

Curcumin, mouse interleukin-2 (mIL-2) (2.5×108 U/mg), and Concanavalin A (Con A) were purchased from Sigma Chemical Co. (St. Louis, MO). A 100 mmol/L solution of curcumin was prepared in DMSO and all test concentrations were prepared by diluting the appropriate amount of stock solution in tissue culture medium.

Mice

Eight to ten-week-old male C3H (H-2k) and C57BL/6J (H-2b) were purchased from Taconic Laboratories (Germantown, NY). Mice consumed Breeder Diet (W) 8626 (protein, 20.0%; fat, 10.0%; fiber,

Antiproliferative effect of curcumin

The effect of curcumin on proliferation of splenic lymphocytes was examined in 3H-thymidine uptake assay. The desired concentration of curcumin was incorporated into culture medium at the initiation of cultures. The results presented in panels A–C of Fig. 1 demonstrate the effect of curcumin on Con A (A), IL-2 (B), and alloantigen (C) induced proliferation of splenic lymphocytes. There was significant increase in Con A induced proliferation of splenic cells at 6.25 μmol/L curcumin (P<0.001)

Discussion

Curcumin has been used in traditional medicine for centuries in the Indian subcontinent to treat inflammatory disorders such as rheumatoid arthritis, intestinal inflammatory conditions, atherosclerosis, skin wounds, and hepatic and biliary disorders [10], [30]. However, the mechanism of anti-inflammatory action of curcumin is not well understood. In the present study we considered the possibility that the beneficial effects of curcumin against inflammatory disorders are attributed to the

Acknowledgements

This work was supported by a grant from American Institute for Cancer Research.

References (48)

  • W.C Willett

    Diet and health: what should we eat?

    Science

    (1994)
  • L.W Wattenberg

    Inhibition of carcinogenesis by minor dietary constituents

    Cancer Res.

    (1992)
  • S.M Kuo

    Dietary flavonoids and cancer prevention: evidence and potential mechanism

    Crit. Rev. Oncol.

    (1997)
  • F.B Hu et al.

    Dietary fat intake and the risk of coronary heart disease in women

    N. Engl. J. Med.

    (1997)
  • A.J Dugas et al.

    Evaluation of the total peroxy radical-scavenging capacity of flavonoids: structure-activity relationships

    J. Nat. Prod.

    (2000)
  • H.P Ciolino et al.

    Dietary flavonols quercetin and kaempferol are ligands of the aryl hydrocarbon receptor that affect CYP1A1 transcription differentially

    Biochem. J.

    (1999)
  • H.P Ammon et al.

    Pharmacology of Curcuma longa

    Plant Med.

    (1991)
  • M.T Huang et al.

    Inhibitory effects of curcumin on in vitro lipoxygenase and cyclooxygenase activities in mouse epidermis

    Cancer Res.

    (1991)
  • M.T Huang et al.

    Inhibitory effect of curcumin, chlorogenic acid, caffeic acid, and ferulic acid on tumor promotion in mouse skin by 12-O-tetradecanoylphorbol-13 acetate

    Cancer Res.

    (1988)
  • M.T Huang et al.

    Inhibitory effects of curcumin on tumorigenesis in mice

    J. Cell Biochem.

    (1997)
  • A.H Conney et al.

    Some perspectives on dietary inhibition of carcinogenesis: studies with curcumin and tea

    Proc. Soc. Exp. Biol. Med.

    (1997)
  • M.T Huang et al.

    Inhibitory effects of dietary curcumin on forestomach, duodenal, and colon carcinogenesis in mice

    Cancer Res.

    (1994)
  • M.A Azuine et al.

    Chemopreventive effect of turmeric against stomach and skin tumors induced by chemical carcinogens in Swiss mice

    Nutr. Cancer

    (1992)
  • C.V Rao et al.

    Chemoprevention of colon cancer by dietary curcumin, a naturally occurring plant phenolic compound

    Cancer Res.

    (1995)
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