Attenuation of antigen-specific T helper 1 immunity by Neolitsea hiiranensis and its derived terpenoids

Abstract

BackgroundT cells play a pivotal role in the adaptive immunity that participates in a wide range of immune responses through a complicated cytokine network. Imbalance of T-cell responses is involved in several immune disorders. Neolitsea species, one of the biggest genera in the family Lauraceae, have been employed widely as folk medicines for a long time in Asia. Previous phytochemical investigations revealed the abundance of terpenes in the leaves of N. hiiranensis, an endemic Neolitsea in Taiwan, and demonstrated anti-inflammatory activities. However, the effect of N. hiiranensis on the functionality of immune cells, especially T cells, is still unclear. In this study, we utilize in vitro and in vivo approaches to characterize the effects of leaves of N. hiiranensis and its terpenoids on adaptive immune responses.MethodsDried leaves of N. hiiranensis were extracted three times with cold methanol to prepare crude extracts and to isolate its secondary metabolites. The ovalbumin (OVA)-sensitized BALB/c mice were administrated with N. hiiranensis extracts (5–20 mg/kg). The serum and splenocytes of treated mice were collected to evaluate the immunomodulatory effects of N. hiiranensis on the production of OVA-specific antibodies and cytokines. To further identify the N. hiiranensis-derived compounds with immunomodulatory potentials, OVA-primed splenocytes were treated with compounds isolated from N. hiiranensis by determining the cell viability, cytokine productions, and mRNA expression in the presence of OVA in vitro.ResultsCrude extracts of leaves of N. hiiranensis significantly inhibited IL-12, IFN-γ, and IL-2 cytokine productions as well as the serum levels of antigen-specific IgM and IgG2a in vivo. Two of fourteen selected terpenoids and one diterpenoid derived from the leaves of N. hiiranensis suppressed IFN-γ in vitro. In addition, β-caryophyllene oxide attenuated the expression of IFN-γ, T-bet, and IL-12Rβ2 in a dose-dependent manner. N. hiiranensis-derived β-caryophyllene oxide inhibited several aspects of adaptive immune responses, including T-cell differentiation, IFN-γ production, and Th1-assocaited genes.ConclusionAs IFN-γ is the key cytokine secreted by T helper-1 cells and plays a pivotal role in Th1 immune responses, our results suggested that the N. hiiranensis and its terpenoids may possess potential therapeutic effects on Th1-mediated immune disorders.

Immunomodulatory Effects of TaiwaneseNeolitseaSpecies on Th1 and Th2 Functionality

“…However, a comparative study of immunomodulatory properties of different Neolitsea species on immunocompetent cells such as T helper cells has not been demonstrated to date. Our previous reported study found that the leaf extracts of N. hiiranensis significantly inhibited IL-12, IFN- γ , and IL-2 cytokine productions as well as the serum levels of OVA-primed antigen-specific IgM and IgG 2a in vivo [ 27 ]. In the present study, we evaluated the immunomodulatory properties of ten Taiwanese Neolitsea plants on T helper cells.…”

“…Daibucarboline A, isolinderalactone, 7-omethylnaringenin, and prunetin isolated from the roots of N. daibuensis exhibited moderate inhibition of inducible nitric oxide synthase (iNOS) [ 40 ]. Hiiranlactone B and hiiranlactone D, isolated from the leaves of N. hiiranensis were classified as sesquiterpenes and possessed anti-inflammatory and immunomodulatory effects [ 27 , 34 ]. Thaliporphine, the alkaloid of the bark extracts of N. konishii , demonstrated vasoconstricting effects by promoting Ca 2+ entry [ 25 ] and possessed antioxidant, anti-inflammatory, and antiapoptotic activity to prevent cardiovascular system disorder in guinea pigs [ 41 ].…”

“…Isolinderalactone, a sesquiterpenes from the roots of N. villosa , exhibited antitumor activity [ 44 ]. Our recent study reported that N. hiiranensis -derived caryophyllene oxide inhibited several aspects of adaptive immune responses, including T-cell differentiation, IFN- γ production, and Th1-associated genes [ 27 ]. These studies suggested that the immunomodulatory effects of Neolitsea plants are worth further investigation; in addition, the present study aimed to clear how other Taiwanese Neolitsea species modulate the functionality of Th cells by ConA-stimulated splenocytes.…”

“…Sesquiterpenes of the N. parvigemma showed inhibitory effects on platelet aggregation [ 26 ]. Our previous study has shown that leaf extracts of N. hiiranensis and its derived terpenoids possessed immunomodulatory effects via regulation of IFN- γ production [ 27 ]. However, due to the complexity of compositions within Neolitsea species, it is still unclear how other Taiwanese Neolitsea species modulate the functionality of immune cells.…”

Identification of informative features for predicting proinflammatory potentials of engine exhausts

“…Human monocyte THP-1 cells were cultured in RPMI 1640 cell culture medium supplemented with 10% heat-inactivated fetal bovine serum (Hyclone) and 1% penicillin/streptomycin (Gibco) at 37 °C in 5% CO 2 . THP-1 cells (5 × 10 5 cells/well) were treated with different samples in 48-well plates in the presence of lipopolysaccharide (0.5 μg/mL) for 48 h. The supernatants were collected and quantified for TNF-alpha, as an indicator of cell proinflammatory responses, by standard sandwich enzyme-linked immunosorbent assay (ELISA) as previously described [ 21 , 22 ]. The TNF-alpha level in LPS group was designated as 100%, and the levels of TNF-alpha in each group was calculated according to the following formula: where a value over 100% indicates induction and a value smaller than 100% indicates inhibition.…”