Augmentation of immune response by chicoric acid through the modulation of CD28/CTLA-4 and Th1 pathway in chronically stressed mice
Highlights
► The study demonstrates the immune restorative potential of CA in chronically stressed mice. ► Our study reports categorically that CA restores immune response in chronically stressful conditions by modulating the expression of CD28/CTLA-4 receptor on T cells with its ligand B7 that are necessary for the activation/inhibition of T cells. ► CA also upregulates the expression of Th1 cytokines like IL-2, IFN-gamma and IL-12 in chronic stressed conditions. ► The study also shows the normalizing effect of CA on raised corticosterone levels.
Introduction
Stress is defined as any situation capable of perturbing the physiological or psychological homeostasis. While response to stress is a necessary survival mechanism, prolonged stress can have several repercussions affecting behavioral, endocrine and immunological parameters (McEwen, 1998). Stress-induced immunologic alterations have been considered as major cause of increased risk for immune-related diseases, such as cancer, autoimmune disorders, and infection (Iwakabe et al., 1998). The hypothalamic–pituitary–adrenal (HPA) and the sympathetic–adrenal medullary (SAM) axes are the two major pathways through which immune function is altered. Lymphocytes, monocytes or macrophages and granulocytes, exhibit receptors for many neuro-endocrine products of the HPA and SAM axes (Rabin et al., 1996) such as cortisol and catecholamines, which cause changes in cellular trafficking, proliferation, cytokine secretion, antibody production and cytolytic activity (Madden and Livnat, 1991) thus making the body vulnerable to many diseases. Modulation of the immune response in stressful conditions is mediated by a complex network of signals that function in bi-directional communication among the nervous, endocrine and immune systems and also involves interaction of various signaling molecules with several immune cells thereby facilitating the cross-talk between these immune cells to evoke a desired immune response.
Currently, the importance of natural products is increasingly realized in reinstating T-cell and Th1/Th2 homeostasis because of their acclaimed safety associated with prolonged treatment and numerous molecules have come out of ayurvedic base. Chicoric acid (CA) occurs naturally in large number of medicinal plants that are being used in folk medicine since time immemorial. It is also known as dicaffeyltartaric acid and belongs to phenylpropanoids (Zaprometov, 1993). This group of compounds is of special interest because of their high biologic activity (Kurkin, 1996). Chicoric acid is well documented as potent inhibitor of the Type 1 human immunodeficiency virus (HIV-1) integrase which catalyses the integration of HIV DNA copy into the host cell DNA (Robinson et al., 1996). Recently, Tousch D and co-workers from Université Montpellier, France, reported its effects on glucose uptake and insulin secretion in cell studies. It is considered as an active candidate for diabetes (Tousch et al., 2008). It has also been shown to have a stimulatory effect upon phagocytes (Bone, 1998). In this study, we have studied thoroughly role of chicoric acid isolated from Taraxacum officinale in augmenting the immune response in chronically stressed mice and also demonstrated that it stimulates immune response by controlling the expression of CD28/CTLA-4 co-stimulatory molecules and by modulating the expression of Th1 cytokines particularly, IL-12 and IL-10 in chronically stressed mice.
Section snippets
Plant material
For isolation of chicoric acid, T. officinale aqueous extract (aerial part) was clarified by ultrafilteration through a PLAC cellulose acetate filter (Millipore, USA), acidified with 0.1% HCl and concentrated with C-18 cartridges (Waters, USA). The concentrated and purified extract (5 mL) was loaded on LH-20 sephadex column (2 × 90 cm, pharmacia, Sweden) in water to acetic acid solution of 10:1 v/v and washed with same solution. Chicoric acid was eluted with CHCl3 at a rate of 1.5 mL/min in 5 mL
Effect of CA on Con-A and LPS stimulated splenocytes
CA elicited considerable increase in proliferative response in the Con-A stimulated T-lymphocytes as compared to the RSC group. The increase in proliferation was observed in a dose dependent manner, the optimal effect being at 1 mg/kg. A similar effect was seen on LPS primed B-cell proliferation while the relative effect was more apparent on T-cell. Cells grown in the absence of mitogens did not show any proliferation (normal control) (Fig. 2).
Lymphocyte immunophenotyping
Percentage of CD3+, CD4+, and CD8+ T cells decreased
Discussion
Stress is perhaps the most debilitating of all elements to the immune system (Elenkov et al., 1996) and leads to a dysfunctional immune system that opens the door for many health risks. The stress-induced decrease in the lymphocyte subsets and associated decline in cytokines particularly Th1, IL-2 and IFN-gamma, is possibly an important factor that renders the immune system vulnerable to clinical conditions (Iwakabe et al., 1998). IFN-gamma influences Th1 development by mediating IL-12Rβ2 chain
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