Cardiac Glycosides as Immune System Modulators

Abstract

Cardiac glycosides (CGs) are natural steroid compounds occurring both in plants and animals. They are known for long as cardiotonic agents commonly used for various cardiac diseases due to inhibition of Na⁺/K⁺-ATPase (NKA) pumping activity and modulating heart muscle contractility. However, recent studies show that the portfolio of diseases potentially treatable with CGs is much broader. Currently, CGs are mostly studied as anticancer agents. Their antiproliferative properties are based on the induction of multiple signaling pathways in an NKA signalosome complex. In addition, they are strongly connected to immunogenic cell death, a complex mechanism of induction of anticancer immune response. Moreover, CGs exert various immunomodulatory effects, the foremost of which are connected with suppressing the activity of T-helper cells or modulating transcription of many immune response genes by inhibiting nuclear factor kappa B. The resulting modulations of cytokine and chemokine levels and changes in immune cell ratios could be potentially useful in treating sundry autoimmune and inflammatory diseases. This review aims to summarize current knowledge in the field of immunomodulatory properties of CGs and emphasize the large area of potential clinical use of these compounds.

Keywords: NKA signalosome; Th17; anticancer compounds; calreticulin; cardiac steroids; immunogenic cell death; inflammation; interleukin 17; retinoic acid receptor-related orphan receptor γ thymus; sodium-potassium ATPase.

Figure 2

A schematic representation of the Na⁺/K⁺-ATPase (NKA) signalosome. Adapted from [45]. AP1–transcription factor; CGs–cardiac glycosides; EGFR-epidermal growth factor receptor; ERK- extracellular signal-regulated kinase; Grb2-growth factor receptor-bound protein 2; IP₃–inositol triphosphate; IP3R–inositol triphosphate receptor; MEK-mitogen-activated protein kinase kinase; NF-κB-nuclear factor kappa-light-chain-enhancer of activated B cells; PKC–protein kinase C; PLC–phospholipase C; Raf–serine/threonine kinase; Ras–rat sarcoma protein; ROS–reactive oxygen species; Shc–Src homology 2 domain-containing transforming protein 1; Sos–son of sevenless; Src-non-receptor tyrosine kinase.

Figure 1

Physiological action of Na⁺/K⁺-ATPase and Na⁺/Ca²⁺ exchanger compared to the action after treatment with cardiac glycosides (CGs). In homeostasis, Na⁺/K⁺-ATPase pumps three Na⁺ ions out of a cell and two K⁺ ions into the cell. Physiologically Na⁺/Ca²⁺ exchanger imports three Na⁺ ions back into the cell in exchange for one Ca²⁺ ion. When the activity of Na⁺/K⁺ ATPase is blocked by CGs, Na⁺ ions accumulate inside the cell, which leads to a subsequent increase in intracellular Ca²⁺ ion concentration due to activation of the Na⁺/Ca²⁺ exchanger. Inspired and adapted according to ref. [34].

Figure 3

A schematic illustration of immunogenic cell death. The release of damage-associated molecular patterns (DAMPs), and activation of immune cells. ANXA1–annexin A1; APC–antigen-presenting cells; ATP–adenosine triphosphate; CALR–calreticulin; CD–a cluster of differentiation; DC –dendritic cells; ER–endoplasmic reticulum; HMGB-1–high mobility group box 1; HSP90/HSP70– heat shock protein 90/70; IFNγ–interferon γ; IL-interleukin; MHC I/-II–major histocompatibility complex I/II; TLR–Toll-like receptor; P2RX2/7-P2X purinoceptor 2/7; TNF α–tumor necrosis factor α.

Figure 4

Cardiac glycosides at low nanomolar concentrations activate RORγt, whereas at high concentrations they cause RORγt transcriptional inhibition. This influences the production of interleukins (IL) 17 and 22 in T-helper cells expressing IL-17 (Th17). The interleukins promote autoimmune diseases by activating immune cells, such as follicular B-helper T cells (TFH), type 1 and type 2 T-helper cells (Th1, Th2), type 1 regulatory T cells (TR1), and regulatory T cells (Treg). These cells produce IL, interferon γ (IFNγ), or transforming growth factor-beta (TGF-β).