The Immunosuppressive Effect of Gamisanghyulyunbueum through Inhibition of Mitogen-Activated Protein Kinase and Nuclear Factor Activation in MOLT-4 Cells

Abstract

Typical Korean traditional medicines consist of 3 to 15 components that are mixed to minimize side effects and maximize medicinal effects. Traditional medicines appear to exert their pharmacological actions through the synergistic effects of their components and via drug interaction. Therefore, they may modulate biological responses, including immune responses, rather than acting through the direct activity of the individual components. 1,2) Gamisanghyulyunbueum (GSHYBE) is a traditional Oriental herbal medicine prescription, which has been used for the treatment of allergic disorders such as atopic dermatitis and especially, skin related disease.3) However, its mechanism has not been investigated experimentally.Activation of T cells is a very complex process that involves cell-to-cell interactions of several cell surface molecules. Engagement of the T cell antigen receptor (TcR) with the antigen-major histocompatibility complex on antigenpresenting cells triggers a complex TcR signaling cascade that leads to T cell activation and cytokine secretion. 4) In consequence to early protein phosphorylation steps and calcium response, mitogen-activated protein kinases (MAPKs) are activated by phosporylation. The three major family of MAPKs, c-Jun NH 2 -terminal kinases (JNK), extracellular signal-regulated kinases (ERK), and p38 MAPK, are regulated by distinct but cross-talking signaling cascades.5) Such signals culminate in the activation of transcription factors such as nuclear factor-kB (NF-kB) and the nuclear factor of activated T cells (NFAT). [6][7][8] The transcription factor NFAT plays an essential role in IL-2 expression. Among of NFAT family members, NFAT1, NFAT2 (NFATc1), and NFAT4 are involved in the transcriptional activation of genes encoding cytokines including IL-2 and IL-4, and CD40 ligand. 9) NFAT2 is induced following T cell stimulation to the same level as NFAT1; however, in nuclear extracts from activated T cells, nearly all the NFAT that bound to a prove corresponding to the distal NFAT site of the human IL-2 promoter was attributable to NFAT1.10) In contrast to normal T cells, NFAT2 seems to play the major role in driving IL-2 transcription in Jarket T cells.11) NF-kB plays a central role in a number of signaling pathways in many cell types.12) Fundamental processes such as cell growth, apotosis, and development are regulated by NF-kB, and NF-kB is a central mediator of immune, inflammatory, and stress response.13) The predominantly characterized NF-kB complex is a p50-p65 heterodimer, which at rest is retained in the cytoplasm and is associated with an inhibitor molecular, IkB. 7)During T cell activation, IkBa is phosphorylated and becomes ubiquitinated, leading to degradation of IkBa and translocation of NF-kB to the nucleus. These transcription factors bind recognition sites within promoter sequences to induce transcription of cytokines, including IL-2 the major T lymphocyte proliferation factor. 14) Thus, T cell stimulation leads to IL production and proliferation, thereby promoting the adapt...