BBA - Molecular Cell Research (v.1592, #3)

CYTOKINES COME OF AGE by Stefan Rose-John (213-214).

Molecular mechanisms of cytokine receptor activation by Joachim Grötzinger (215-223).
Cytokine receptors are transmembrane proteins that transmit a signal into the cell upon ligand binding. Commonly, these molecules have one hydrophobic segment of about 20–26 amino acids that is believed to span the membrane as a helix and this divides these receptors into extra- and intracellular components. By utilizing two different epitopes, the cytokines bridge two receptor chains, resulting in a close proximity of the intracellular component and thereby initiating the intracellular signalling cascade. The dimerization event is believed to be the mechanism by which the signal is transmitted across a membrane. In the light of new results obtained for the erythropoietin receptor, James A. Wells questioned whether any dimer would be sufficient. This review will expand upon the above question by discussing the more complex signal-transducing receptor subunits of the Interleukin-6 type family of cytokines. Based on the recently solved quaternary structure of the Insulin receptor, possible analogies will be confronted.
Keywords: Cytokine receptor; gp130; Dimerization; Activation;

A structural template for gp130-cytokine signaling assemblies by Dar-chone Chow; Lena Brevnova; Xiao-lin He; Monika M Martick; Alex Bankovich; K.Christopher Garcia (225-235).
The gp130-cytokine system has been fertile ground for protein structure–function studies aimed at elucidating the basis of ligand recognition and receptor activation. A number of longstanding questions involve the mechanism of the stepwise assembly of the active signaling complexes, as well as the structure of the gp130-cytokine complexes. It has been clear from functional studies that the paradigm of gp130-cyokine recognition will differ substantially from the classical homo-dimeric systems, typified by human growth hormone (hGH) and its receptor. Recently, a crystal structure of a viral interleukin-6 (vIL-6), complexed with the D1D2D3 domains of the gp130 extracellular domain, has resolved many of these questions, and reconciled much of the functional and mutagenesis data which have existed for a variety of gp130-cytokines. In this review, we discuss the structure of the vIL-6/gp130 complex in some detail and suggest that the geometry of this complex will be a common structural template utilized by other gp130-cytokines, as well as cytokines from distinct signaling systems.
Keywords: Cytokine; Structure; Receptor; Complex; Recognition; Signaling; X-ray crystallography;

Structure, binding, and antagonists in the IL-4/IL-13 receptor system by Thomas D Mueller; Jin-Li Zhang; Walter Sebald; Albert Duschl (237-250).
Interleukin-4 (IL-4) and IL-13 are the only cytokines known to bind to the receptor chain IL-4Rα. Receptor sharing by these two cytokines is the molecular basis for their overlapping biological functions. Both are key factors in the development of allergic hypersensitivity, and they also play a major role in exacerbating allergic and asthmatic symptoms. Knowledge of structure and function of this system has allowed the development of inhibitors that block the interaction between the cytokines and their shared receptor. Mutational analysis of IL-4 has revealed variants with high-affinity binding to IL-4Rα but no detectable affinity for the second receptor subunit, which is either γc or IL-13Rα1. These IL-4 antagonists fail to induce signal transduction and block IL-4 and IL-13 effects in vitro. IL-4 antagonists prevent the development of allergic disease in vivo and an antagonistic variant of human IL-4 is now in clinical trials for asthma. Detailed knowledge of the site of interaction of IL-4 and IL-4Rα has been gained by structure analysis of the complex of these two proteins and through functional studies employing mutants of IL-4 and its receptor subunits. Based on these new data, the hitherto elusive goal of designing small molecular mimetics may be feasible.
Keywords: IL-4; IL-13; Allergy; Antagonist; Protein structure;

Cytokines perform ever-increasing roles in both, the regulation of general homeostasis and in orchestrating the immune response during disease. To ensure that control of the cytokine network is tightly regulated, nature has developed a series of systems designed for this purpose. In this respect, researchers have placed considerable emphasis on identifying and characterising the regulatory properties of soluble cytokine receptors. These proteins bind their ligands with similar affinities to those of their cognate transmembrane receptors and are effective at prolonging the circulating half-life of cytokines they bind. However, it is the individual capacity of these soluble receptors to act as either antagonists or agonists which has been the principal focus of most research studies. This review provides an overview of the activities of soluble cytokine receptors, but primarily concentrates on those that possess agonistic properties.
Keywords: Receptor; Cytokine; sIL-6R/IL-6 complex;

The Toll/interleukin-1 (IL-1) receptor (TIR) family comprises two groups of transmembrane proteins, which share functional and structural properties. The members of the IL-1 receptor (IL-1R) subfamily are characterized by three extracellular immunoglobulin (Ig)-like domains. They form heterodimeric signaling receptor complexes consisting of receptor and accessory proteins. The members of the Toll-like receptor (TLR) subfamily recognize alarm signals that can be derived either from pathogens or the host itself. TLRs possess leucine-rich repeats in their extracellular part. TLRs can form dimeric receptor complexes consisting of two different TLRs or homodimers in the case of TLR4. The TLR4 receptor complex requires supportive molecules for optimal response to its ligand lipopolysaccharide (LPS). A hallmark of the TIR family is the cytoplasmic TIR domain that is indispensable for signal transduction. The TIR domain serves as a scaffold for a series of protein–protein interactions which result in the activation of a unique signaling module consisting of MyD88, interleukin-1 receptor associated kinase (IRAK) family members and Tollip, which is used exclusively by TIR family members. Subsequently, several central signaling pathways are activated in parallel, the activation of NFκB being the most prominent event of the inflammatory response. Recent developments indicate that in addition to the common signaling module MyD88/IRAK/Tollip, other molecules can modulate signaling by TLRs, especially of TLR4, resulting in differential biological answers to distinct pathogenic structures. Subtle differences in TLR signaling pathways are now becoming apparent, which reveal how the innate immune system decides at a very early stage the direction in which the adaptive immune response will develop. The creation of pathogen-specific mediator environments by dendritic cells defines whether a cellular or humoral response will be activated in response to the pathogen.
Keywords: Interleukin-1 receptor signaling; Interleukin-18 receptor signaling; Toll-like receptor signaling; Interleukin-1 receptor associated kinase; Innate immunity;

Molecular basis of the cell specificity of cytokine action by Katsuhiko Ishihara; Toshio Hirano (281-296).
The molecular cloning and biological analyses of cytokines have led us to a general understanding of their pleiotropism and redundancy. These features have been ascribed to the composition of cytokine receptor complexes, which include a signal-transducing receptor subunit that is used by all members of a cytokine family and a binding subunit that is specific for each cytokine. Even though a given cytokine uses the same receptor complex when binding to various cell types, the cytokine elicits quite specific and distinct biological responses in different types of cells. Even in the same type of cell, the responses to a given cytokine could vary depending on the location of the cell and the condition of its microenvironment. Important mediators for the main cytokine signal-transduction pathway are the Janus kinases (Jaks) and signal transducer and activator of transcription (STATs). Selective usage of members of the Jak and STAT families by a given cytokine receptor is partly responsible for the specificity of cytokine action. In addition to the Jak–STAT pathway, a cytokine receptor complex can simultaneously operate multiple signal-transduction pathways, which usually express contradictory properties. These contradictory signals from a single cytokine are orchestrated to evoke a unified biological response in the cell. Here we discuss the molecular mechanisms that regulate how the cell specificity of cytokine signals is regulated, especially focusing on the IL-6/gp130 system.
Keywords: IL-6; gp130; STAT; SHP-2; Gab1; Gab2;

Cytokines and growth factors are important extracellular regulatory proteins. They exert their biological functions through binding to their cognate receptors on the cell surface and triggering intracellular signaling cascades. However, the intracellular signaling mechanisms of cytokines and growth factors are not well understood. Accumulating evidence has shown that protein phosphorylation and dephosphorylation carried out by protein kinases and protein phosphatases are fundamental biochemical events in intracellular signal transduction. SHP-2, a Src homology (SH) 2 domain-containing protein tyrosine phosphatase (PTP), is widely involved in a variety of signaling pathways triggered by cytokines and growth factors, including the MAP kinase, Jak-Stat, and PI3 kinase pathways. Recent studies have clearly demonstrated that this phosphatase plays an important role in transducing signals relayed from the cell surface to the nucleus, and is a critical intracellular regulator in cytokine and growth factor-induced cell survival, proliferation, and differentiation.
Keywords: SHP-2; Protein tyrosine phosphatase; Cytokine; Signaling;

Cytokine regulation of liver development by Taisei Kinoshita; Atsushi Miyajima (303-312).
Liver development is a sequential array of distinct biological events. Each step of differentiation is regulated by intrinsically programmed mechanisms as well as by extracellular signals. The establishment of cell culture systems that recapitulate each stage of liver development has led to the identification of several extracellular signals that affect hepatocytic differentiation. Furthermore, studies on genetically engineered animals, especially knockout and transgenic mice, have highlighted a number of molecules essential for liver development. By applying primary culture techniques to analyses of mutant mice, it is now possible to link extracellular signals to intracellular pathways that provoke cellular responses of differentiation. Improvement in gene transfer technology utilizing viral vectors has further expanded the molecular analysis of liver development. In this review article, we summarize recent advances and attempt to describe the molecular basis of liver development from beginning to end as a sequential event.
Keywords: Cytokine; Liver; Development;

Ex vivo expansion of hematopoietic stem cells by cytokines by Toshio Heike; Tatsutoshi Nakahata (313-321).
Keywords: Expansion; Stem cell; Cytokine;

The activation of cells that do not express the membrane bound interleukin-6 6 receptor (IL-6R) by IL-6 and the soluble IL-6 receptor (sIL-6R) is termed transsignalling. Transsignalling may be an pathogenetic factor in human diseases as diverse as multiple myeloma (MM), Castleman's disease, prostate carcinoma, Crohn's disease, systemic sclerosis, Still's disease, osteoporosis and cardiovascular diseases. IL-6 and sIL-6R may directly or indirectly enhance their own production on endothelial or bone marrow stromal cells. Positive feedback autocrine loops thus created in affected organs may either cause or maintain disease progression. In autoimmune or vasculitic disease, the ability of the IL-6/sIL-6R complex to inhibit apoptosis of autoreactive T-cells may be central to the development of tissue specific autoimmunity. The anti-apoptotic effect of the IL-6/sIL-6R complex may be involved in tumour genesis and resistance to chemotherapy.Only in rare cases, where counterregulation has failed, there is a notable systemic effect of IL-6/sIL-6R. Appropriate animal models are necessary to establish the pathogenetic role of the IL-6/sIL-6R complex. A specific treatment option for diseases influenced by the sIL-6R could be based on gp130–Fc, a soluble gp130 (sgp130) linked to the Fc-fragment of IgG1. gp130–Fc has shown efficacy in vivo in animal models of Crohn's disease.
Keywords: Interleukin-6; Transsignalling; Soluble receptor; Disease; Treatment; Autoimmunity;

The liver is a unique organ, and first in line, the hepatocytes encounter the potential to proliferate during cell mass loss. This phenomenon is tightly controlled and resembles in some way the embryonal co-inhabitant cell lineage of the liver, the embryonic hematopoietic system. Interestingly, both the liver and hematopoietic cell proliferation and growth are controlled by various growth factors and cytokines. IL-6 and its signaling cascade inside the cells through STAT3 are both significantly important for liver regeneration as well as for hematopoietic cell proliferation. The process of liver regeneration is very complex and is dependent on the etiology and extent of liver damage and the genetic background. In this review we will initially describe the clinical relevant condition, portraying a number of available animal models with an emphasis on the relevance of each one to the human condition of fulminant hepatic failure (FHF). The discussion will then be focused on the role of cytokines in liver failure and regeneration, and suggest potential new therapeutic modalities for FHF. The recent findings on the role of IL-6 in liver regeneration and the activity of the designer IL-6/sIL-6R fusion protein, hyper-IL-6, in particular, suggest that this molecule could significantly enhance liver regeneration in humans, and as such could be a useful treatment for FHF in patients.
Keywords: Cytokine; Liver; Regeneration; Stem cells;