Nuclear Factor-kappa B Signaling Pathways and Parasitic Infections: An Overview

Host nuclear factor-kappa B (NF-κB) transcription factor plays a pivotal role in innate immunity and resistance to infection. It induces the expression of several genes that encode pro-inflammatory cytokines. It also participates in regulating the differentiation and survival of innate immune cells and lymphocytes. Infection of host cells with pathogens usually activates host NF-κB signaling pathways. The majority of parasites evolved diverse protective mechanisms against NF-κB activity to shield their continued existence. Herein, we present brief insights into NF-κB signaling pathways, activators and inhibitors, and the main subsequent events following protozoan and helminthic infections in vitro, as well as in vivo either in experimental models, or in humans. Understanding the underlying mechanisms of NF-κB activation and inhibition may be of great help as a therapeutic strategy against different parasitic infections. Abbreviations: DCs: Dendritic cells; ECs: Endothelial cells; ESPs: Excretory-secretory products; IKK: Inhibitor of nuclear factorkappa B kinase; IKKα: Inhibitor of NF-κB kinase-α; IKKβ: Inhibitor of NF-κB kinase-β; IL: Interleukin; iNOS: Inducible nitric oxide synthase; IκB: Inhibitor of NF-κB; IκBα: Inhibitor of NF-κB-α; LPS: Lipopolysaccharide; NF-κB: Nuclear factor-kappa B; NO: nitric oxide; TLR: Toll-like receptor; TNF-α: Tumor necrosis factor-α. Nuclear factor-κB and parasitic infections Alhusseiny and El-Beshbishi 219 with immune and inflammatory responses, whereas the latter is a secondary signaling pathway concerned with controling adaptive immunity, B cell function, and lymphoid organ development[1]. Activators of the classical pathway include lipopolysaccharide (LPS), tumor necrosis factor-α (TNF-α), or interleukin (IL)-1β, that attach to specific receptors. Sequences include IKKβ-mediated phosphorylation of IκBα that becomes degraded through the proteasome releasing p50/p65 dimers. On the other hand, the alternative pathway is induced by B-cell activating factor (BAFF) or lymphotoxin β. It includes IKKα activation through NF-κB inducing kinase (NIK), p100 phosphorylation by IKKα, and its processing by the proteasome to yield p52. Next steps include liberation of RelB/p52 dimers, nuclear translocation, and triggering specific genes, which are different from the genes controlled by the classical pathway. In the atypical pathway, hypoxic injury or oxidative stress (DNA damage) leads to massive IκBα phosphorylation via p38-induced casein kinase-2 (CK-2) and release of p50/p65 dimers[9]. Role of NF-κB signaling in immune response and inflammatory process Extensive studies have been conducted on NF-κB signaling pathways owing to its major role in activating plentiful genes implicated in the infection response. Cell surface toll-like receptors (TLRs) expressed via dendritic cells (DCs), mucosal epithelial cells, and macrophages are the main component of the innate immune response that identifies pathogens (cell wall LPS and nucleic acids)[10]. Once triggered, all TLRs endorse the NF-κB signaling pathways[11]. These NF-κB pathways elicit macrophage inflammatory protein-1α (MIP-1α), pro-inflammatory cytokines (e.g. TNF-α, IL-1, and IL-6), besides adhesion molecules such as vascular cell adhesion molecule-1 and E-selectin expression[10]. It was reported that E-selectin belongs to cell adhesion molecules that are expressed by cytokines-activated endothelial cells (ECs). It is designated as CD62E, and is recognized to have chief effects during the inflammation response[12]. After release, TNF-α and IL-1 reactivate NF-κB pathway, with further response augmentation. Moreover, NF-κB activates B and T lymphocytes receptors (co-stimulatory and antigen), besides supporting the survival and differentiation of B cells through B-cell activating factor activity[13]. Inhibition of NF-κB signaling pathways In most cells, activation of NF-κB pathway is usually a temporary process (~30-60 min). Persistent NF-κB signaling is inhibited by down-regulation of NF-κB within a feedback loop (negative feedback). The gene that encodes IκBα is provoked by NF-κB, and newlyformed IκBα enters the nucleus, eliminates NF-κB from DNA, and sends the complex again to the cytoplasm. There, NF-κB is retained till further activation[13]. Dysregulation of NF-κB is associated with diverse health problems, e.g. multiple sclerosis, cerebral stroke, Alzheimer's disease, atherosclerosis, bronchial asthma, diabetes mellitus, viral infections, and genetic disorders. Proper control of NF-κB signaling through pharmacological or genetic therapies represents a novel strategy for the management of NF-κB related disorders[14]. Interestingly, NF-κB signaling pathways can be prevented through many pharmacological agents that inhibit NF-κB activity at different levels including: • Non-steroidal anti-inflammatory drugs (e.g. sodium salicylate and aspirin) act by inhibiting cytokine and endotoxin-induced nuclear translocation of NF-κB through preventing phosphorylation and proteolysis of IκBα[15]. Besides, they can serve as IKK inhibitors and act by specifically inhibiting ATP-binding to IKKβ. Consequently, they markedly decrease IKKβ-dependent phosphorylation, and prevent both IKKβ proteasomal degradation and NFκB pathway activation[16]. • Steroids (e.g. glucocorticoids) that directly interact with NF-κB and activator protein-1 (AP-1), and produce independent transrepression complexes. They can also provoke the expression of IκBα and hold NF-κB in the cytoplasm[17]. Fig. 1. Nuclear factor-kappa B signaling pathways. Activators of NF-κB bind corresponding receptors and activate IKKβ in the classical pathway and IKKα via NIK in alternative pathway. DNA damage acts through p38 and CK-2. Kinases phosphorylate IκBα, and p100. Active dimers of NF-κB are released, translocate to the nucleus, and bind DNA to start target genes transcription. Illustrated by Alhusseiny SM. BAFF: B-cell activating factor; CK-2: Casein kinase-2; IκBα: Inhibitor of NF-κB-α; IKKα: Inhibitor of NF-κB kinase-α; IKKβ: Inhibitor of NF-κB kinase-β; IL-1β: Interleukin-1β; LPS: Lipopolysaccharide; NIK: NF-κB inducing kinase; P: Phosphorylation; TNF-α: Tumour necrosis factor-α. Alternative pathwy BAFF, Lymphotoxin β Classical pathwy LPS, TNF-α, IL-1β Alternative pathwy Hypoxic injury or oxidative stress (DNA damage)