Matrine Induces Cell Anergy in Human Jurkat T Cells through Modulation of Mitogen-Activated Protein Kinases and Nuclear Factor of Activated T-Cells Signaling with Concomitant Up-Regulation of Anergy-Associated Genes Expression

Abstract

T cell activation plays a pivotal role in the pathogenesis of human autoimmune and chronic inflammatory illnesses. In the past decades, great efforts have been made to find immunosuppressants that can intervene in T cell activation and proliferation. However, in treatment of some refractory cases of these illnesses, immunosuppressants must be taken for long-term, even life-long, in spite of various side effects. Therefore, T cell immunotolerance induction leading to T cells anergy has been becoming a promising new therapeutic strategy for autoimmune conditions. Such agents typically have few side effects because they act only as adjuvants in the human body to induce T cell anergy in response to unknown antigens. In fact, T cell activation in the body requires engagement of both the T cell receptor (TCR) and CD28 on the cells through participation of the major histocompatibility complex (MHC) peptides and B7 family members on antigen presenting cells (APC). When T cells are stimulated by antigen(s) through TCR in the absence of CD28/B7, the cells develop long-term hyporesponsiveness to subsequent stimulations 1) ; this is known as T cell anergy. In other words, T cell anergy is an immunotolerance condition in which T cells are intrinsically and functionally inactivated following encounter with antigen(s); the cells remain alive but hyporesponsive for an extended period of time.2) Furthermore, this hyporesponsiveness is characterized by a suppression of interleukin (IL)-2 secretion, such that T cell activation and proliferation are in turn inhibited.1) Thus, agents that stimulate TCR alone and suppress IL-2 secretion before T cells are activated by antigen(s) are likely ideal candidates for use as T cell immunotolerance inducers.Although detailed molecular mechanisms of T cell anergy remain unclear, it is well-known that it is partially mediated through calcineurin and the nuclear factor of activated T-cells (NFAT).3) In the resting T cells, NFAT proteins are phosphorylated and reside in the cytoplasm. When the cells were stimulated, NFAT proteins are dephosphorylated by calcineurin and then translocated into the nucleus and become the transcriptional active, and thus providing a direct line between intracellular Ca 2ϩ signaling and gene expression. 4)Especially, when T cells received TCR/CD28 stimulation, NFAT will be dephosphorylated, translocated into nucleus and cooperated with AP-1, the transcriptional partner of NFAT which is composed of heterodimers of Fos-and Junfamily protein, to induce many genes encoding cytokines, chemokines and other products in the immune responses. Different from NFAT, the activators of AP-1 are mitogen-activated protein kinases (MAPKs) including c-Jun NH 2 -terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38 kinase. In contrast, when NFAT was preactivated by Ca 2ϩ signals or TCR stimulation alone without co-stimulation provided by CD28 and thus in the absence of its transcriptional factor AP-1, the T cell anergy will be induced. 5)To date, the optimum and sim...

Casitas B Lineage Lymphoma b Is a Key Regulator of Peripheral Tolerance in Systemic Lupus Erythematosus

“…Although anergy has been associated with decreased activation of TCR-associated kinases, such as Akt, PI3K, PKC, and MAPK (ERK-1/2) (43)(44)(45), other studies have demonstrated either no differences or increased activation levels of these kinases in anergic cells (29,34,46). The current evidence supports a model in which the main hallmark of the anergic state is a block in G1-to-S progression during the cell cycle (34,47,48).…”

Matrine pretreatment improves cardiac function in rats with diabetic cardiomyopathy via suppressing ROS/TLR-4 signaling pathway

“…The herb's clinical effects were believed to be dependent on its active molecule, C 15 H 24 N 2 O, an alkaloid also known as matrine ( Figure 1). Matrine has many biological activities and exerts many biological effects, such as anti-inflammation, anti-fibrosis, and immune regulation [10][11][12] . Although they are rarely mentioned, the anti-oxidant properties of matrine have been described in www.nature.com/aps Liu ZW et al Acta Pharmacologica Sinica npg previous studies [13] .…”

Matrine Induces Apoptosis in Human Acute Myeloid Leukemia Cells via the Mitochondrial Pathway and Akt Inactivation

“…Matrine, an alkaloid extracted from Sophora flavescens Aif, is quinolizidine with four-loop and molecular formula of C 15 H 24 N 20 . Matrine has been found to exhibit many biological activities, such as anti-inflammation, anti-virus, anti-fibrosis, anti-arrhythmia, and immunosuppression, leading to wide clinical use in the treatment of viral hepatitis, liver fibrosis, heart arrhythmia and skin diseases in China [6]–[11]. Recently, intensive studies have shown that matrine possesses potent antitumor activities by inhibiting proliferation and inducing apoptosis of cells from gastric cancer, lung cancer, hepatocellular carcinoma, breast cancer, melanoma, leukemia, multiple myeloma [12]–[21].…”