Elsevier

Biochemical Pharmacology

Volume 77, Issue 4, 15 February 2009, Pages 508-520
Biochemical Pharmacology

Review
Growth factors, cytokines and their receptors as downstream targets of arylhydrocarbon receptor (AhR) signaling pathways

https://doi.org/10.1016/j.bcp.2008.09.013Get rights and content

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental pollutant, which causes a variety of severe health effects, e.g. immunosuppression, hepatotoxicity, and carcinogenesis. The main mediator of TCDD toxicity is the arylhydrocarbon receptor (AhR), which, upon activation, translocates into the nucleus and enforces gene expression. Since most of the pleiotropic effects caused by TCDD are associated with alterations in cell growth and differentiation, the analysis of the interference of the AhR with factors controlling these cellular functions seems to be a promising target regarding the prevention and treatment of chemical-provoked diseases. Cell growth and differentiation are regulated by numerous growth factors and cytokines. These multifunctional peptides promote or inhibit cell growth and regulate differentiation and other cellular processes, depending on cell-type and developmental stage. They are involved in the regulation of a broad range of physiological processes, including immune response, hematopoiesis, neurogenesis, and tissue remodeling. The complex network of growth factors and cytokines is accurately regulated and disturbances of this system are associated with adverse health effects. The molecular mechanisms by which the AhR interferes with this signaling network are multifaceted and the physiological consequences of this cross-talk are quite enigmatic. The investigation of this complex interaction is an exciting task, especially with respect to the recently described non-genomic and/or ligand-independent activities of AhR. Therefore, we summarize the current knowledge about the interaction of the AhR with three cytokine-/growth factor-related signal transducers – the epidermal growth factor (EGF) family, tumor necrosis factor-α (TNF-α), and transforming growth factor-β (TGF-β) – with regard to pathophysiological findings.

Introduction

Halogenated polyaromatic hydrocarbons (PAHs) like dibenzo-p-dioxins, dibenzo-p-furans and polychlorinated biphenyls are widespread industry- and combustion-derived environmental pollutants, which embody an alerting risk potential for human health. Among them, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most potent toxicant, causing immunological abnormalities, teratogenic and carcinogenic effects, wasting syndrome, alterations in the endocrine system and hepatotoxicity in several species [1]. In humans the most conspicuous effect of TCDD intoxication is chloracne, caused by alterations in differentiation and proliferation of epidermal cells. The fact that several others of the mentioned adverse effects of TCDD, for example its tumor promoting property, are also based on modified patterns in differentiation and proliferation, strengthens the idea that TCDD influences growth factor-dependent cellular pathways.

Growth factors and cytokines are peptide regulatory factors which are essential for cell fate and function, since they are involved in all aspects of cell differentiation, survival, proliferation, senescence and apoptosis [2]. Growth factors and cytokines are expressed and secreted by almost all tissues, even though cytokines were originally defined as signaling peptides of the hematopoietic and immune system, respectively. Growth factors and cytokines act in autocrine and paracrine loops and exert multiple actions on various, sometimes common, target structures. One main function of cytokines and growth factors is the activation of transcription factors, which modulate the cellular gene expression pattern and subsequently alter cell function [2]. For these actions specific membrane receptors are required. Numerous in vivo and in vitro studies reported about TCDD-mediated modifications of growth factor and cytokine signaling. For instance, changes in transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-2, IL-6, IL-8 and interferon-γ gene expression rates were noted upon TCDD exposure [3], [4], [5], [6]. However, even if the underlying molecular mechanisms for this transcriptional modulation of cytokines and growth factors are not fully understood, it is broadly accepted that the arylhydrocarbon receptor (AhR), at least in part, is involved in the regulation of these TCDD-induced changes in gene expression [7], [8], [9].

The AhR is a chemosensor for halogenated PAHs and related xenobiotics, which belongs to the basic helix–loop–helix Per-ARNT-Sim (bHLH/PAS) protein superfamily. In its non-activated form, the cytosolic AhR is bound to several chaperones like heat-shock protein 90 (hsp90), p23 and the AhR interacting protein (AIP) [1]. Upon ligand binding, the AhR translocates into the nucleus, dimerizes with ARNT (AhR nuclear translocator) and enforces gene transcription via binding to xenobiotic-responsive elements (XREs) within the promoter sequences of target genes. The AhR gene battery consists of genes encoding for phase I and II drug metabolizing enzymes, with cytochrome P450 (CYP) 1A1 as the most prominent one, as well as for proteins involved in regulation of cell growth and differentiation [1]. Another AhR target gene is the AhR repressor, a regulatory component of AhR signaling, which is capable of blocking XRE-mediated gene expression in a competitive way.

In this review article we summarize the current knowledge about the molecular interaction of the activated AhR molecule with several cytokine- and growth factor-driven signaling pathways. The main focus is on the interference of the AhR with TGF-β, TNF-α, the family of epidermal growth factors (EGF) and their respective receptors, since these molecules are closely associated with our recent research interests. Early milestones and scientific strategies as well as today’s open questions regarding this complex field of AhR biology are discussed.

Section snippets

Interference of AhR-dependent pathways with the EGF receptor (EGFR) and its ligands

EGF and the group of related (EGF-like) growth factors are extracellular protein ligands for specific cell-surface receptors, called the ErbB family, which convert extracellular signals into biological responses [10], [11]. The common structural motifs of the ErbB proteins are an extracellular ligand-binding domain, a hydrophobic transmembrane domain and a cytoplasmic domain harboring tyrosine kinase activity [11]. The probably most prominent ErbB receptor is ErbB-1, also known as epidermal

Cross-talk between TNF-α- and AhR-driven signal transduction

The multifunctional cytokine TNF-α was described for the first time by the physician William B. Coley nearly a century ago. Decades later two cytotoxic factors produced by lymphocytes and macrophages were characterized on molecular level: lymphotoxin and TNF-α[65]. This comparison revealed striking similarities of both signaling molecules regarding structure and biological function. Today the search term “tumor necrosis factor” results in nearly 90,000 hits in PubMed, pointing to the enormous

Interaction of the TGF-β family with the AhR pathway

The mammalian transforming growth factor family represents a large group of multifunctional cytokines that control various cellular functions, like tissue homeostasis and repair, cell growth, apoptosis and immune response. It consists of three TGF-β isoforms, activin, and the bone morphogenetic proteins. The TGF-β isoforms (TGF-β1, TGFβ2, TGFβ3) are important inhibitors of epithelial cell growth and are prominent players in cancer, cardiovascular diseases and immune response [92], [93]. In this

Concluding remarks

Cytokines and growth factor are implicated in many physiological and pathological processes. Disturbances of the balance of their orchestra of interaction could provoke disastrous consequences for cell and tissue homeostasis, respectively. As discussed, the AhR and its ligands are capable of interfering in manifold ways with cytokine and growth factor signaling cascades. The clarification of the underlying mechanisms will provide new opportunities to develop preventive and therapeutic

Acknowledgement

We thank Dr. Ulrich Sydlik for critical revision of the manuscript.

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